Methods, Compounds, and Compositions for the Treatment of Angiotensin-Related Diseases

ABSTRACT

Disclosed are small molecule non-peptidic compounds, as well as methods and compositions for the treatment of angiotensin-related diseases and disorders, including cardiovascular diseases, metabolic diseases, gastrointestinal diseases, renal diseases, inflammatory/autoimmune diseases, neurological diseases, bone marrow diseases and cancer. In particular, the invention provides compounds, methods and compositions for the treatment of metabolic diseases and disorders, such as diabetes mellitus, diabetes-related cardiovascular disorders, diabetes-related dermal ulcerations, diabetes related hypertension, and diabetes-related ophthalmic diseases.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/773,041, filed Sep. 4, 2015, which is a U.S. national phaseapplication of International Patent Application No. PCT/US2014/030071,filed on Mar. 15, 2014, which claims priority to U.S. ProvisionalApplication No. 61/809,290 filed Apr. 5, 2013 and U.S. ProvisionalApplication Ser. No. 61/802,259 filed Mar. 15, 2013, the disclosures ofwhich are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to novel heteroaryl non-peptidic compounds thatmimic the heptapeptide angiotensin (1-7) [Ang(1-7)] and act as agonistsof the Mas receptor, especially in a selective manner. The inventionfurther relates to methods of using such compounds as therapeuticagents, in particular for the treatment of angiotensin-related diseasesor disorders, to pharmaceutical compositions containing such compounds,and to synthetic routes for the preparation of such compounds.

BACKGROUND OF THE INVENTION

A wide range of physiological and pathophysiological conditions arerelated to the renin-angiotensin system (RAS), which is an importantregulator of arterial blood pressure and involves the formation andactions of several angiotensin peptides (FIG. 1). The major angiotensinpeptides include the decapeptide angiotensin I(Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu), the octapeptide angiotensinII (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), the heptapeptide angiotensin (1-7)(Asp-Arg-Val-Tyr-Ile-His-Pro) and the hexapeptide angiotensin IV(Val-Tyr-Ile-His-Pro-Phe).

The angiotensin peptides and the related enzymes and receptors play keyroles in the cardiovascular system, the renal system, the hematopoieticsystem, the hepatobiliary system, the pulmonary system, thegastrointestinal system, the nervous system, and in many other criticalphysiological and pathophysiological pathways, in part, throughstimulation of stem cell activity (FIG. 1). Renin acts onangiotensinogen to form angiotensin I (AngI), which is cleaved byangiotensin converting enzyme (ACE) to form angiotensin II (AngII), andby neutral endopeptidases to form Ang(1-7), which is also produced fromAngII via cleavage by ACE2.

The three G-protein coupled receptors (GPCR) that mediate many of theactions of the angiotensin peptides are the AngII type 1 receptor(AT1R), the AngII type 2 receptor (AT2R), and the Mas receptor (Mas)known as the native receptor for Ang(1-7). The activation ordeactivation of these receptors play major roles in numerous tissues,including the heart, blood vessels, liver, kidney and the brain. Thedevelopment of selective antagonists for AT1R provided multipleimportant therapeutics for heart disease and other conditions. Morerecently, the elucidation of the beneficial actions of the AT2R led toselective agonists for AT2R as potential therapeutics.

This invention discloses a new class of small molecule mimetics ofAng(1-7) that are able to bind and activate the Mas receptor, and canserve as potential therapeutics for a wide range of angiotensin-relateddiseases. Ang(1-7) acts as an endogenous agonist of the Mas receptor,and was shown to have a number of important beneficial actions.

Ang(1-7) was shown to modulate pathways impacted by obesity anddiabetes, and has been shown to exert beneficial effects in end organdamage in diabetes and hypertension (Benter et al., 2006; 2007; Singh etal., 2011). In a rat model of metabolic syndrome, elevated circulatinglevels of Ang(1-7) enhanced glucose tolerance, insulin sensitivity anddecreased dyslipidemia (Santos et al., 2010; Marcus et al., 2012).Ang(1-7) further improves heart function in diabetic animals and aftermyocardial infarction and reverses diabetes-induced bone marrowsuppression (Loot et al., 2002; Langeveld et al., 2008; Ebermann et al,2008). In a Phase II clinical trial, a peptide analogue of Ang(1-7) wasshown to reduce diabetic complication of non-healing foot ulcers(Balingat et al, 2012). Although this peptide may have potential use inthe reduction of diabetes and insulin resistance, daily peptideinjections may not be the optimal route of administration to ensurepatient adherence in a chronic disease. Therefore, there remains a needfor small molecule mimics of Ang(1-7) that can be effectively used tocontrol diabetes with improved patient adherence.

Ang(1-7) and its peptide analogs are non-hypertensive regenerativefactors in clinical trials for accelerating healing of hematopoietic anddermal injuries. A pharmaceutical formulation of Ang(1-7) was shown tobe safe for clinical use, and was found to stimulate bone marrow andhematopoietic recovery (Rodgers et al, 2002, 2006 and Pham et al 2013).Ang(1-7) was shown to be active in several models of tissueregeneration. The actions of Ang(1-7) are hypothesized to occur throughproduction of arachidonic acid metabolites, nitric oxide (NO), orbradykinin (BK) metabolites (Albrect 2007; Ribeirio-Olivera et al.,2008; Dias-Peixoto et al., 2008). NO is involved in protection fromorgan failure in diabetes and in the actions of modulators of the RAS inimproved outcomes in diabetics (Kosugi et al., 2010). Ang(1-7) may alsoreduce end organ damage in diabetes through stimulation of PPARγ, thepathway stimulated by several therapeutics used to reduce insulinresistance in diabetes (Dhaunsi et al., 2010).

The native receptor for Ang(1-7) is the GPCR Mas, where the geneticdeletion of Mas abolished Ang(1-7) binding. Accordingly, Ang(1-7) wasable to bind to Mas-transfected cells and elicited arachidonic acidrelease. In addition, Mas KO mice do not have an anti-naturetic andwater volume changes and Ang(1-7) binding in the kidney. Furthermore,Mas-deficient aortas lost their Ang(1-7)-induced relaxation response(Santos et al., 2003). The benefits of Ang(1-7) to accelerate recoveryof myelosuppression and reduce chronic inflammation in diabetics aremediated through Mas.

Despite some progress and extensive efforts there is still a need fornew therapeutics that might be effective in preventing diabetes,reducing diabetic complications, and treating diabetes-relatedconditions. The current treatment for diabetes includes the use ofantidiabetic agents such as insulin, biguianides, thiazolidinediones,non-sulfonylurea secretagogues, and peptide analogs. Current treatmenttargets reduction of circulating glucose through supplementing insulinsecretion or increase cellular sensitivity to insulin activation.Despite managing circulating glucose, the co-morbidity associated withdiabetes continues, albeit at a slower progression. This includesdevelopment cardiovascular disorders such as atherosclerosis,hypertension, congestive heart failure, and cerebral ischemia. Inability to control diabetes have also been linked to other organdysfunction including renal dysfunction, diabetic retinopathy, andneurological dysfunction. These co-morbid conditions may be aconsequence of uncontrolled chronic inflammation that may be promoted byuncontrolled glucotoxicity or insulin-resistance.

Despite extensive efforts that led to the successful design anddevelopment of antagonists for the AngII receptor 1 (AT1R), known asangiotensin receptor blockers (ARBs), similar studies to identifyagonists of AT2R and Mas receptors have been limited. A few notableexamples are the AT2R agonist compound 21 and related compounds(Steckeling et al., 2011), the Mas agonist AVE-0991 (Santos et al.,2006), and certain Mas modulator derivatives (Zhang et al., 2012).

The discovery of effective mimetics of Ang(1-7) that activate the Masreceptor in a potent and selective manner has remained a challenge.Molecules of this type are of great interest, and are expected to finduse for the treatment of several major diseases for which there is anunmed medical need.

BRIEF SUMMARY OF THE INVENTION

One aspect of this invention provides heteroaryl non-peptidic compoundsthat mimic the heptapeptide angiotensin (1-7) and act as agonists of theMas receptor, especially in a selective manner. The invention furtherprovides methods of using such compounds as therapeutic agents, inparticular for the treatment of angiotensin-related diseases ordisorders and related conditions. The invention also providespharmaceutical compositions containing such compounds, and syntheticroutes for their preparation.

In one embodiment, compounds according the present invention havegeneral formula 1 and includes salts thereof:

wherein:

-   -   ring A is a five-membered or six-membered heteroaryl or        heterocyclyl ring containing either a combination of two        non-adjacent nitrogen or oxygen atoms, or a combination of three        or four nitrogen or oxygen atoms;    -   ring B is a five-membered or six-membered heteroaryl ring that        contains at least one nitrogen atom;    -   ring C is an optionally substituted aryl ring;    -   A¹, A², A³, A⁴ are independently selected from a group        consisting of =N—, —C(═O)—, —C(R^(a))═, ═C(R^(b))—,        —C(R^(c))(R^(d))—N(R^(e))—, —C(R^(c))(R^(d))—O—, or        —[C(R^(c))(R^(d))]_(n)— with n being 1 or 2;    -   X¹—X² is (R⁶)C—N, N—C(R⁶), N—N, N—O, O—N, N—S or S—N;    -   X³ is (R⁷)C═C(R⁸), O, S, or N(R⁹);    -   Z is O, NH or a bond to R⁵;    -   R^(a) and R^(b) are independently selected from the group        consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy,        aryloxy, formyl, acyl, acylamido or carboxy, provided that R^(a)        and R^(b) can also join to form a ring of up to 6 atoms;    -   R^(c) and R^(d) are independently selected from a group        consisting of hydrogen, alkyl, aryl, or heteroaryl, provided        that R^(c) and R^(d) can also join to form a ring of up to 6        atoms;    -   R^(e) is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,        aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;    -   R¹, R³, R⁴, R⁶, R⁷, and R⁸ are independently selected from a        group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo,        cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl,        or aryloxyalkyl;    -   R² is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl,        heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy,        aryloxy, alkoxyalkyl, or aryloxyalkyl;    -   R⁵ is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl,        alkoxyalkyl, or aryloxyalkyl; and    -   R⁹ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,        aminoacyl, dialkylaminoacyl, or dialkylaminoacyl.

In a second embodiment, the invention provides methods for thepreparation of the provided compounds.

In a third embodiment, the invention provides pharmaceuticalcompositions comprising one or more provided compounds in apharmaceutically acceptable carrier.

In a fourth embodiment, the invention provides compounds that act asnon-peptidic mimetics of Ang(1-7) or as effective agonists of the Masreceptor.

In a fifth embodiment, the invention provides methods for the treatmentof angiotensin-related diseases or disorders and related conditions.

In a sixth embodiment, the provided methods and compositions areemployed in oral, parenteral, or topical administration comprising of aprovided compound or a pharmaceutically acceptable salt, and apharmaceutically acceptable carrier.

In particular, the invention provides methods and compositions for thetreatment of angiotensin-related diseases or disorders and relatedconditions, upon oral, parenteral (e.g. subcutaneous, intrathecal,epidural, intravenous, intraocular) and topical administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: The Renin-Angiotensin System (RAS). This figure lists the majorRAS angiotensin peptides and highlights their biosynthesis and thetarget receptors that mediate these peptides' biological activities.

FIG. 2: Binding motifs of the provided compounds at a homology model ofAT2R. (A) Chemical structure of exemplary compound 7. (B) Model ofcompound 7 docked into an AT2R homology model. For clarity, the modelsof this Figure show only an ethyl group in place of the butyl group ofcompound 7. (C) Contact residues at the binding site of compound 7 atAT2R. (D) Overall orientation of compound 7 in its binding site at AT2R.(E) Contact residues at the binding site of the pyrazole isomer ofcompound 7 at AT2R. (F) Contact residues at the binding site of aclosely related compound to exemplary compound 7, where the pyridinering is replaced with a benzene ring. (G) Model of the compound shown in(F) docked into an AT2R homology model. For clarity, the models of thisFigure show only an ethyl group in place of the butyl group of compound7. (H) Overall orientation of compound shown in (F) in its binding siteat AT2R.

FIG. 3: Binding motifs of the provided compounds at a homology model ofthe Mas receptor. (A) Contact residues at the binding site of exemplarycompound 7 at the Mas receptor. (B) Model of compound 7 docked into aMas receptor homology model, showing selected residues involved in thebinding site. For clarity, the models of this Figure show only an ethylgroup in place of the butyl group of compound 7. (C)-(D) Overallorientation of compound 7 in its binding site at the Mas receptor.

FIG. 4: Mas stably transfected CHO was compared Ang(1-7) with compound7, revealing a concentration dependent increase in NO as measured by thelevel of fluorescence (A). Mas agonist activity was confirmed whenco-administered with A779, an antagonist of Mas, blocked both Ang(1-7)and compound 7 back to baseline fluorescence.

FIG. 5: Fasting blood glucose (FBG) was evaluate in db/db animalstreated for 14 days with vehicle, 500 μg/kg/day Ang(1-7) and compound 7.Compound 7 was able to reduce peripheral glucose >40% of levels found invehicle or Ang(1-7) treated mice (A).

FIG. 6: Compound 7 can prevent organmegaly in db/db animals. Theseanimals were treated with 14 days with vehicle, 500 μg/kg Ang(1-7), or500 μg/kg/day compound 7. Compound 7 treated animals were able toprevent the development of cardiomegaly (A) and left kidney hypertrophy(B), where the difference between db/db controls was statisticallysignificant (p<0.05). The right kidney trended to be similar toheterozygous control, and lower than db/db controls (C).

FIG. 7: Lipid levels in the liver was evaluated in db/db animals treatedfor 14 days with vehicle, 500 μg/kg/day Ang(1-7) and compound 7. Liverfrom compound 7 (right panel) treated mice had a reduced Oil Redstaining (red droplets reflect lipid deposition) when compared withdb/db controls (treated with saline) (left panel).

FIG. 8: Diabetes causes a reduction in the health of the bone marrow,the source of a number of progenitors that participate in healing,particularly blood cells (red cells, platelets and leukocytes).Treatment with both Ang(1-7) and compound 7 increased the bone marrowcounts is (A). Additionally Compound 7 was comparable to Ang(1-7) in theincrease in bone marrow cell number as well as early progenitors(CFU-GEMM), myeloid progenitors (CFU-GM), erythroid progenitors (BFU-E)and mesenchymal stem cells (MSC) (B-E).

FIG. 9: The effect of compound 7 on tumor cell proliferation wasevaluated using MDA MB 231 in a concentration escalation design.Compound 7 did not increase proliferation of MDA MB 231 breast cancercell line. Rather compound 7 inhibited tumor proliferation with an IC50calculated to be 58 μM.

FIG. 10: The uptake and distribution of intravenous of compound 7 wasmeasured in the blood of C57Bl/6 mice. Animals were euthanized atvarious time points after administration of compound 7 and bloodcollected and processed to plasma. Concentrations of compound 7 weremeasured by LC-MS/MS methodology. The oral bioavailability of compound 7was 30%.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there is a plurality of definitions for a term herein, thosein this section will control unless stated otherwise.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. is usedas is generally understood by those of skill in the chemical art. Asused in this specification, alkyl groups can include straight-chained,branched and cyclic alkyl radicals containing up to about 20 carbons, or1 to 16 carbons, and are straight or branched. Exemplary alkyl groupsherein include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl,neopentyl, tert-pentyl and isohexyl. As used herein, lower alkyl referto carbon chains having from about 1 or about 2 carbons up to about 6carbons. Suitable alkyl groups may be saturated or unsaturated. Further,an alkyl may also be substituted one or more times on one or morecarbons with substituents selected from a group consisting of C1-C15alkyl, allyl, allenyl, alkenyl, C3-C7 heterocycle, aryl, halo, hydroxy,amino, cyano, oxo, thio, alkoxy, formyl, carboxy, carboxamido,phosphoryl, phosphonate, phosphonamido, sulfonyl, alkylsulfonate,arylsulfonate, and sulfonamide. Additionally, an alkyl group may containup to 10 heteroatoms, in certain embodiments, 1, 2, 3, 4, 5, 6, 7, 8 or9 heteroatom substituents. Suitable heteroatoms include nitrogen,oxygen, sulfur and phosphorous.

As used herein, “cycloalkyl” refers to a mono- or multicyclic ringsystem, in certain embodiments of 3 to 10 carbon atoms, in otherembodiments of 3 to 6 carbon atoms. The ring systems of the cycloalkylgroup may be composed of one ring or two or more rings which may bejoined together in a fused, bridged or spiro-connected fashion.

As used herein, “aryl” refers to aromatic monocyclic or multicyclicgroups containing from 3 to 16 carbon atoms. As used in thisspecification, aryl groups are aryl radicals, which may contain up to 10heteroatoms, in certain embodiments, 1, 2, 3 or 4 heteroatoms. An arylgroup may also be optionally substituted one or more times, in certainembodiments, 1 to 3 or 4 times with an aryl group or a lower alkyl groupand it may be also fused to other aryl or cycloalkyl rings. Suitablearyl groups include, for example, phenyl, naphthyl, tolyl, imidazolyl,pyridyl, pyrroyl, thienyl, pyrimidyl, thiazolyl and furyl groups.

As used in this specification, a ring is defined as having up to 20atoms that may include one or more nitrogen, oxygen, sulfur orphosphorous atoms, provided that the ring can have one or moresubstituents selected from the group consisting of hydrogen, alkyl,allyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro,hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, thalkylamino,acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio,alkylsulfonate, arylsulfonate, phosphoryl, phosphonate, phosphonamido,and sulfonyl, and further provided that the ring may also contain one ormore fused rings, including carbocyclic, heterocyclic, aryl orheteroaryl rings.

The term “alkenyl” refers to a branched or unbranched hydrocarbon havingat least one carbon-carbon double bond.

The term “alkynyl” refers to a branched or unbranched hydrocarbon havingat least one carbon-carbon triple bond.

The term “carboxy” refers to a —CO₂H group.

The term “hydroxy” refers to an —OH group.

The term “alkoxy” refers a group of the formula R—O— where R is an“alkyl” as defined herein.

The term “carbocycle” refers to a non-aromatic stable 3- to 8-memberedcarbon ring which may be saturated, mono-unsaturated orpoly-unsaturated.

The term “amino” includes primary, secondary or tertiary amino groups.

The term “cyano” refers to the group —CN.

As used herein, alkenyl and alkynyl carbon chains, if not specified,contain from 2 to 20 carbons, or 2 to 16 carbons, and are straight orbranched. Alkenyl carbon chains of from 2 to 20 carbons, in certainembodiments, contain 1 to 8 double bonds, and the alkenyl carbon chainsof 2 to 16 carbons, in certain embodiments, contain 1 to 5 double bonds.Alkynyl carbon chains of from 2 to 20 carbons, in certain embodiments,contain 1 to 8 triple bonds, and the alkynyl carbon chains of 2 to 16carbons, in certain embodiments, contain 1 to 5 triple bonds.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system, in certain embodiments, of about 4 to about 15members where one or more, in one embodiment 1 to 4, of the atoms in thering system is a heteroatom, that is, an element other than carbon,including but not limited to, nitrogen, oxygen or sulfur. The heteroarylgroup may be optionally fused to a benzene ring. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrrolidinyl,pyrimidinyl, triazolyl, tetrazolyl, thienyl, pyridyl, pyrrolyl,N-methylpyrrolyl, quinolinyl and isoquinolinyl.

As used herein, “heterocyclyl” refers to a monocyclic or multicyclicnon-aromatic ring system, in one embodiment of 3 to 10 members, inanother embodiment of 4 to 7 members, in a further embodiment of 5 to 6members, where one or more, in certain embodiments, 1 to 3, of the atomsin the ring system is a heteroatom, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen or sulfur. Inembodiments where the heteroatom(s) is(are) nitrogen, the nitrogen isoptionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl,aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, acyl, guanidino, or the nitrogen may be quaternizedto form an ammonium group where the substituents are selected as above.

As used herein, “aralkyl” refers to an alkyl group in which one of thehydrogen atoms of the alkyl is replaced by an aryl group.

As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Br or I.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by halogen. Such groups include,but are not limited to, chloromethyl and trifluoromethyl.

As used herein, “aryloxy” refers to RO—, in which R is aryl, includinglower aryl, such as phenyl.

As used herein, “acyl” refers to a —COR group, including for examplealkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, or heteroarylcarbonyls,all of which may be optionally substituted.

As used herein “subject” is an animal, typically a mammal, includinghuman, such as a patient.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944).

As used herein, pharmaceutically acceptable derivatives of a compoundinclude salts, esters, enol ethers, enol esters, acetals, ketals,orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydratesor prodrugs thereof. Such derivatives may be readily prepared by thoseof skill in this art using known methods for such derivatization. Thecompounds produced may be administered to animals or humans withoutsubstantial toxic effects and either are pharmaceutically active or areprodrugs. Pharmaceutically acceptable salts include, but are not limitedto, amine salts, such as but not limited toN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole,diethylamineand other alkylamines, piperazine andtris(hydroxymethyl)aminomethane; alkali metal salts, such as but notlimited to lithium, potassium and sodium; alkali earth metal salts, suchas but not limited to barium, calcium and magnesium; transition metalsalts, such as but not limited to zinc; and other metal salts, such asbut not limited to sodium hydrogen phosphate and disodium phosphate; andalso including, but not limited to, salts of mineral acids, such as butnot limited to hydrochlorides and sulfates; and salts of organic acids,such as but not limited to acetates, lactates, malates, tartrates,citrates, ascorbates, succinates, butyrates, valerates and fumarates.Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkyl and heterocyclyl esters of acidic groups, including, but notlimited to, carboxylic acids, phosphoric acids, phosphinic acids,sulfonic acids, sulfinic acids and boronic acids. Pharmaceuticallyacceptable enol ethers include, but are not limited to, derivatives offormula C═C(OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl ar heterocyclyl.Pharmaceutically acceptable enol esters include, but are not limited to,derivatives of formula C═C(OC(O)R) where R is hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl arheterocyclyl. Pharmaceutically acceptable solvates and hydrates arecomplexes of a compound with one or more solvent or water molecules, or1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent orwater molecules.

As used herein, the term “treatment” means any manner in which one ormore of the symptoms of a disease or disorder are ameliorated orotherwise beneficially altered. Treatment also encompasses anypharmaceutical use of the compositions herein, such as use for treatinga disease as provided herein.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

B. Compounds

As set forth above, this invention provides compounds, methods andcompositions for the treatment of angiotensin-related diseases anddisorders.

The provided compounds are able to act selectively at certain GPCRreceptors.

This invention provides compounds of the general formula 1 and saltsthereof:

wherein:

-   -   ring A is a five-membered or six-membered heteroaryl or        heterocyclyl ring containing either a combination of two        non-adjacent nitrogen or oxygen atoms, or a combination of three        or four nitrogen or oxygen atoms;    -   ring B is a five-membered or six-membered heteroaryl ring that        contains at least one nitrogen atom;    -   ring C is an optionally substituted aryl ring;    -   A¹, A², A³, A⁴ are independently selected from a group        consisting of ═N—, —C(═O)—, —C(R^(a))═, ═C(R^(b))—,        —C(R^(c))(R^(d))—N(R^(e))—, —C(R^(c))(R^(d))—O—, or        —[C(R^(c))(R^(d))]_(n)— with n being 1 or 2;    -   X¹—X² is (R⁶)C—N, N—C(R⁶), N—N, N—O, O—N, N—S or S—N;    -   X³ is (R⁷)C═C(R⁸), O, S, or N(R⁹);    -   Z is O, NH or a bond to R⁵;    -   R^(a) and R^(b) are independently selected from the group        consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy,        aryloxy, formyl, acyl, acylamido or carboxy, provided that R^(a)        and R^(b) can also join to form a ring of up to 6 atoms;    -   R^(c) and R^(d) are independently selected from a group        consisting of hydrogen, alkyl, aryl, or heteroaryl, provided        that R^(c) and R^(d) can also join to form a ring of up to 6        atoms;    -   R^(e) is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,        aminoacyl, dialkylaminoacyl, or dialkylaminoacyl;    -   R¹, R³, R⁴, R⁶, R⁷, and R⁸ are independently selected from a        group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo,        cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl,        or aryloxyalkyl;    -   R² is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl,        heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy,        aryloxy, alkoxyalkyl, or aryloxyalkyl;    -   R⁵ is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl,        alkoxyalkyl, or aryloxyalkyl; and    -   R⁹ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,        aminoacyl, dialkylaminoacyl, or dialkylaminoacyl.    -   In some preferred embodiments, R² is trifluoromethoxy.    -   In other preferred embodiments, Z is O, NH.    -   In exemplary embodiments, ring A includes but is not limited to        a ring selected from a group consisting of:

wherein:

-   -   R¹⁰ and R¹¹ are independently selected from a group consisting        of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo,        hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl,        acyl, acylamido or carboxy, provided that R¹⁰ and R¹¹ can also        be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl        ring;    -   R¹² is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,        halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or        acylamido;    -   R¹³ is hydrogen, alkyl, aryl or heteroaryl;    -   R¹⁴ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,        aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and    -   R^(f), R^(g), R^(h), and R^(i), are independently selected from        a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo,        hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or        aryloxyalkyl.

In other exemplary embodiments, ring B includes but is not limited to afive- or six-membered heteroaryl ring selected from a group consistingof:

wherein groups R⁶, R⁷, R⁸ and R⁹ are defined as in general formula 1

In some exemplary embodiments, the provided compounds have the generalformula selected from a group consisting of:

wherein groups R¹, R², R³, R⁴R⁵, R⁶, R⁷, R⁸, R⁹, A¹, A², A³, A⁴ and Zare defined as in general formula 1.

In other exemplary embodiments, the provided compounds have the generalformula selected from a group consisting of:

wherein:

-   -   R¹, R², R³, R⁴R⁵, R⁶, R⁷, R⁸, R⁹, R^(a), R^(b), R^(c), R^(d) and        Z are defined as in general formula 1.    -   R¹⁰ and R¹¹ are independently selected from a group consisting        of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo,        hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl,        acyl, acylamido or carboxy, provided that R¹⁰ and R¹¹ can also        be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl        ring;    -   R¹² is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,        halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or        acylamido;    -   R¹³ is hydrogen, alkyl, aryl or heteroaryl;    -   R¹⁴ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,        aminoacyl, thalkylaminoacyl, or dialkylaminoacyl; and    -   R^(f), R^(g), R^(h), and R^(i), are independently selected from        a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo,        hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or        aryloxyalkyl.

In additional exemplary embodiments, the provided compounds have thegeneral formula selected from a group consisting of:

wherein:

-   -   R¹, R², R³, R⁴R⁵, R⁶, R⁷, R⁸, R⁹, R^(a), R^(b), R^(c), R^(d) and        Z are defined as in general formula 1.    -   R¹⁰ and R¹¹ are independently selected from a group consisting        of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo,        hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl,        acyl, acylamido or carboxy, provided that R¹⁰ and R¹¹ can also        be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl        ring;    -   R¹² is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,        halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or        acylamido;    -   R¹³ is hydrogen, alkyl, aryl or heteroaryl;    -   R¹⁴ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,        aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and    -   R^(f), R^(g), R^(h), and R^(i), are independently selected from        a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo,        hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or        aryloxyalkyl.

In some preferred embodiments, the provided compounds have the generalformula 2a,b or 3a,b:

wherein:

-   -   R¹, R², R³, R⁴R⁵, R⁶, R⁷, R⁸, R⁹, R^(a), R^(b), R^(e), R^(d) and        Z are defined as in general formula 1.    -   R¹⁰ and R¹¹ are independently selected from a group consisting        of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo,        hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl,        acyl, acylamido or carboxy, provided that R¹⁰ and R¹¹ can also        be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl        ring;    -   R¹² is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,        halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or        acylamido;    -   R¹³ is hydrogen, alkyl, aryl or heteroaryl;    -   R¹⁴ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,        aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and    -   R^(f), R^(g), R^(h), and R^(i), are independently selected from        a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo,        hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or        aryloxyalkyl.

In further preferred embodiments the invention provides compounds havingthe general formula 4a,b, 5a,b or 6a,b:

wherein:

-   -   R¹, R², R³, R⁴R⁵, R⁶, R⁷, R⁸, R⁹, R^(a), R^(b), R^(e), R^(d) and        Z are defined as in general formula 1.    -   R¹⁰ and R¹¹ are independently selected from a group consisting        of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo,        hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl,        acyl, acylamido or carboxy, provided that R¹⁰ and R¹¹ can also        be joined to form a carbocyclic, heterocyclic, aryl or hetoaryl        ring;    -   R¹² is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,        halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or        acylamido;    -   R¹⁴ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl,        aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and    -   R¹⁵ is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl,        trifluoromethyl or pentafluoroethyl; and    -   R¹⁶ is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl,        alkynyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino.

In some exemplary embodiments, the R¹⁰, R¹¹ and R¹² are hydrogen, andR¹⁴ is methyl.

In other exemplary embodiments, R¹⁵ is trifluoromethyl and R¹⁶ is ethyl.

Exemplary embodiments are provided by compounds 7, 8, 9, 10, and 11:

C. Preparation of the Compounds

The compounds provided herein may be prepared by methods known in theart or by the general methods known in the art and exemplified herein inthe provided Examples 2-5.

The provided compounds of formula 1 can be prepared via two alternativemethods, which involve combinations of two intermediates.

The first method for the preparation of compounds of formula 1 beginswith Step 1 that involves the bromination of the heteroaryl bromideintermediate Ia to form intermediate Ib. In Step 2, intermediate Ib isreacted with the amine intermediate containing ring A of formula Ic toform intermediate Id. In Step 3, intermediate Id is reacted with theboronic acid or boronate intermediate of formula Ie (having a borongroup B(OR)₂ wherein R is H, or alkyl) under palladium-mediated crosscoupling conditions to form intermediate of formula If. In Step 4, thet-butyl protecting group of intermediate If is removed and the remainingfunctional group is introduced via methods known in the art to formcompound of formula 1.

Step 1:

Step 2:

Step 3:

Step 4:

The second method involves a different order of these steps. In Step 1the boronic acid or boronate intermediate of formula Ie is reacted withthe heteroaryl bromide of formula Ia under palladium-mediated crosscoupling condition to form intermediate Ig. In Step 2 intermediate Ig isbrominated to form intermediate Ih. In Step 3 intermediate Ih is reactedwith the amine intermediate containing ring A of formula Ic to formintermediate If. In Step 4, (described above) the t-butyl protectinggroup of intermediate If is removed and the remaining functional groupis introduced via methods known in the art to form compound of formula1.

Step 1:

Step 2:

Step 3:

In a modified method intermediate Id is prepared via a reductiveamination of aldehyde intermediate Ii with amine intermediate Ic.

In another modified method intermediate If is prepared via a reductiveamination of aldehyde intermediate Ij with amine intermediate Ic.

D. Formulation of Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of compounds provided herein or theirsalts thereof in a pharmaceutically acceptable carrier.

The compositions contain one or more compounds provided herein or theirsalts thereof. The compounds are preferably formulated into suitablepharmaceutical preparations such as solutions, suspensions, tablets,dispersible tablets, pills, capsules, powders, sustained releaseformulations or elixirs, for oral, buccal, intranasal, vaginal, rectal,ocular administration or in sterile solutions or suspensions forparenteral administration, as well as transdermal patch preparation anddry powder inhalers. Typically the compounds described above areformulated into pharmaceutical compositions using techniques andprocedures well known in the art (see, e.g., Ansel Introduction toPharmaceutical Dosage Forms, Fourth Edition 1985, 126).

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable derivatives is (are) mixed with asuitable pharmaceutical carrier or vehicle. The compounds may bederivatized as the corresponding salts, esters, enol ethers or esters,acids, bases, solvates, hydrates or prodrugs prior to formulation, asdescribed above. The concentrations of the compounds in the compositionsare effective for delivery of an amount, upon administration, thattreats, prevents, or ameliorates one or more of the symptoms ofconditions including, but not limited to, cardiovascular disease(myocardial infarction, congestive heart failure, diabeticcardiovascular disease, atrial fibrillation, hypertension, peripheralvascular disease, erectile dysfunction, stroke, pre-eclampsia, coatedstents to inhibit restenosis, Marfan syndrome, and abdominal/thoracicaortic aneurysm), metabolic diseases (insulin resistance and metabolicsyndrome), renal diseases (diabetic renal disease, drug-induced renalfailure, and chronic renal failure), pulmonary diseases (pulmonaryfibrosis, acute lung injury, pulmonary hypertension, and asthma),inflammatory and autoimmune diseases (arthritis, Crohn's disease, graftversus host disease, systemic sclerosis and multiple sclerosis),neurological diseases (depression, anxiety, dementia, Alzheimer'sdisease, neurodegenerative diseases, traumatic brain injury, peripheralneuropathy, spinal cord injury, and Huntington's disease),musculoskeletal diseases (muscular dystrophy and muscular injury),fibrotic diseases (scar reduction, pulmonary fibrosis, liver fibrosisand cardiac fibrosis), dermal diseases (wound healing, radiationmitigation, dermal repair, scar reduction, and alopecia), oculardiseases (macular degeneration, corneal scarring, and diabeticretinopathy), liver diseases (non alcoholic hepatosteatosis, hepaticfibrosis, hepatobilliary disease, fatty liver disease, cirrhosis, andliver fibrosis), oncology and related diseases (cancer and supportivecare for oncology), gastrointestinal disease (stress ulcers and Crohn'sdisease), and bone marrow diseases (recovery from myelosuppression dueto radiation or chemotherapy, autologous transplant, radiationmitigation, engraftment of transplant, allogenic transplant,engraftment, hematopoiesis and bone marrow injury, and myelodysplasticsyndromes).

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. For example,liposome formulations may be prepared as described in U.S. Pat. No.4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV's) maybe formed by drying down egg phosphatidyl choline and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of acompound provided herein in phosphate buffered saline lacking divalentcations (PBS) is added and the flask shaken until the lipid film isdispersed. The resulting vesicles are washed to remove unencapsulatedcompound, pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems described hereinand then extrapolated therefrom for dosages for humans.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical characteristics of the compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to ameliorate one or more of the symptoms ofdiseases or disorders associated including but not limited tocardiovascular disease (myocardial infarction, congestive heart failure,diabetic cardiovascular disease, atrial fibrillation, hypertension,peripheral vascular disease, erectile dysfunction, stroke,pre-eclampsia, coated stents to inhibit restenosis, Marfan syndrome, andabdominal/thoracic aortic aneurysm), metabolic diseases (insulinresistance and metabolic syndrome), renal diseases (diabetic renaldisease, drug-induced renal failure, and chronic renal failure),pulmonary diseases (pulmonary fibrosis, acute lung injury, pulmonaryhypertension, and asthma), inflammatory and autoimmune diseases(arthritis, Crohn's disease, graft versus host disease, systemicsclerosis and multiple sclerosis), neurological diseases (depression,anxiety, dementia, Alzheimer's disease, neurodegenerative diseases,spinal cord injury, traumatic brain injury, peripheral neuropathy andHuntington's disease), musculoskeletal diseases (muscular dystrophy andmuscular injury), fibrotic diseases (scar reduction, pulmonary fibrosis,liver fibrosis and cardiac fibrosis), dermal diseases (wound healing,radiation mitigation, dermal repair, scar reduction, and alopecia),ocular diseases (macular degeneration, corneal scarring, and diabeticretinopathy), liver diseases (non alcoholic hepatosteatosis, hepaticfibrosis, hepatobilliary disease, fatty liver disease, cirrhosis, andliver fibrosis), oncology and related diseases (cancer and supportivecare for oncology), gastrointestinal disease (stress ulcers and Crohn'sdisease), and bone marrow diseases (recovery from myelosuppression dueto radiation or chemotherapy, autologous transplant, radiationmitigation, engraftment of transplant, allogenic transplant,engraftment, hematopoiesis and bone marrow injury, and myelodysplasticsyndromes).

Typically a therapeutically effective dosage should produce a serum orplasma concentration of active ingredient of from about 0.1 ng/ml toabout 50-100 μg/ml. The pharmaceutical compositions typically shouldprovide a dosage of from about 0.001 mg to about 100 mg of compound perkilogram of body weight per day. Pharmaceutical dosage unit forms areprepared to provide from about 1 mg to about 2,000 mg and preferablyfrom about 10 to about 200 mg of the essential active ingredient or acombination of essential ingredients per dosage unit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Pharmaceutically acceptable derivatives include acids, bases, enolethers and esters, salts, esters, hydrates, solvates and prodrug forms.The derivative is selected such that its pharmacokinetic properties aresuperior to the corresponding neutral compound.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating or preventingdiseases or disorders associated with cardiovascular disease (myocardialinfarction, congestive heart failure, diabetic cardiovascular disease,atrial fibrillation, hypertension, peripheral vascular disease, erectiledysfunction, stroke, pre-eclampsia, coated stents to inhibit restenosis,Marfan syndrome, and abdominal/thoracic aortic aneurysm), metabolicdiseases (insulin resistance and metabolic syndrome), renal diseases(diabetic renal disease, drug-induced renal failure, and chronic renalfailure), pulmonary diseases (pulmonary fibrosis, acute lung injury,pulmonary hypertension, and asthma), inflammatory and autoimmunediseases (arthritis, Crohn's disease, graft versus host disease,systemic sclerosis and multiple sclerosis), neurological diseases(depression, anxiety, dementia, Alzheimer's disease, neurodegenerativediseases, spinal cord injury, traumatic brain injury, peripheralneuropathy, and Huntington's disease), musculoskeletal diseases(muscular dystrophy and muscular injury), fibrotic diseases (scarreduction, pulmonary fibrosis, liver fibrosis and cardiac fibrosis),dermal diseases (wound healing, radiation mitigation, dermal repair,scar reduction, and alopecia), ocular diseases (macular degeneration,corneal scarring, and diabetic retinopathy), liver diseases (nonalcoholic hepatosteatosis, hepatic fibrosis, hepatobilliary disease,fatty liver disease, cirrhosis, and liver fibrosis), oncology andrelated diseases (cancer and supportive care for oncology),gastrointestinal disease (stress ulcers and Crohn's disease), and bonemarrow diseases (recovery from myelosuppression due to radiation orchemotherapy, autologous transplant, radiation mitigation, engraftmentof transplant, allogenic transplant, engraftment, hematopoiesis and bonemarrow injury, and myelodysplastic syndromes). The concentration ofactive compound in the composition will depend on absorption,inactivation, excretion rates of the active compound, the dosageschedule, amount administered, particular formulation as well as otherfactors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including orally, parenterally, intravenously, vaginal, intranasal,buccal, sublingual, rectally, ocularly, topically and locally. For oraladministration, capsules and tablets are presently preferred. Thecompositions are in liquid, semi-liquid or solid form and are formulatedin a manner suitable for each route of administration. Preferred modesof administration include parenteral and oral modes of administration.Oral administration is presently most preferred.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, hydroxyethyl cellulose (HEC), β-cyclodextin, hydroxypropylβ-cyclodextrin, carboxymethyl cellulose colloidal solutions,hydroxyethyl cellulose colloidal solutions polyethylene glycol,glycerine, propylene glycol or other synthetic solvent; antimicrobialagents, such as benzyl alcohol and methyl parabens; antioxidants, suchas ascorbic acid and sodium bisulfite; chelating agents, such asethylenediaminetetraacetic acid (EDTA); buffers, such as acetates,citrates and phosphates; and agents for the adjustment of tonicity suchas sodium chloride or dextrose. Parenteral preparations can be enclosedin ampules, disposable syringes or single or multiple dose vials made ofglass, plastic or other suitable material.

In another embodiment, the bioactive lipid(s) are administered in apolymer formulation, including but not limited toPoly-D,L-Lactic-Co-Glycolic Acid (PLGA), poly-lactic acid (PLA),PLA-PLGA co-polymers, polycaprolactone particles, and chitosannanoparticles.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease, disorder or condition treatedand may be empirically determined.

Pharmaceutical compositions of the present invention may beadvantageously provided for administration to humans and animals in unitdosage forms, such as tablets, capsules, pills, powders, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds or pharmaceutically acceptable derivatives thereof. Thepharmaceutically therapeutically active compounds and derivativesthereof are typically formulated and administered in unit-dosage formsor multiple-dosage forms. Unit-dose forms as used herein refer tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit-dose contains apredetermined quantity of the therapeutically active compound sufficientto produce the desired therapeutic effect, in association with therequired pharmaceutical carrier, vehicle or diluent. Examples ofunit-dose forms include ampules and syringes and individually packagedtablets or capsules. Unit-dose forms may be administered in fractions ormultiples thereof. A multiple-dose form is a plurality of identicalunit-dosage forms packaged in a single container to be administered insegregated unit-dose form. Examples of multiple-dose forms includevials, bottles of tablets or capsules or bottles of pints or gallons.Hence, multiple dose form is a multiple of unit-doses which are notsegregated in packaging.

The composition can contain, along with the active ingredient, a diluentsuch as lactose, sucrose, dicalcium phosphate, orcarboxymethylcellulose; a lubricant, such as magnesium stearate, calciumstearate and talc; and a binder such as starch, natural gums, such asgum acacia, gelatin, glucose, molasses, polvinylpyrrolidine, cellulosesand derivatives thereof, povidone, crospovidones and other such bindersknown to those of skill in the art. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing an active compound as defined above andoptional pharmaceutical adjuvants in a carrier, such as, for example,water, saline, aqueous dextrose, glycerol, glycols, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, acetate, sodium citrate, cyclodextrine derivatives,sorbitan monolaurate, triethanolamine sodium acetate, triethanolamineoleate, and other such agents. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, contain a quantity of the activecompound in an amount sufficient to alleviate the symptoms of thetreated subject.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non-toxic carrier may beprepared. For oral administration, a pharmaceutically acceptablenon-toxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions may contain 0.001%-100% activeingredient, preferably 0.1-85%, typically 75-95%.

The active compounds or pharmaceutically acceptable derivatives may beprepared with carriers that protect the compound against rapidelimination from the body, such as time-release formulations orcoatings.

The compositions may include other active compounds to obtain desiredcombinations of properties. The compounds provided herein, orpharmaceutically acceptable derivatives thereof as described herein, mayalso be advantageously administered for therapeutic or prophylacticpurposes together with another pharmacological agent known in thegeneral art to be of value in treating one or more of the diseases ormedical conditions referred to hereinabove, including but not limted tocardiovascular disease (myocardial infarction, congestive heart failure,diabetic cardiovascular disease, atrial fibrillation, hypertension,peripheral vascular disease, erectile dysfunction, stroke,pre-eclampsia, coated stents to inhibit restenosis, Marfan syndrome, andabdominal/thoracic aortic aneurysm), metabolic diseases (insulinresistance and metabolic syndrome), renal diseases (diabetic renaldisease, drug-induced renal failure, and chronic renal failure),pulmonary diseases (pulmonary fibrosis, acute lung injury, pulmonaryhypertension, and asthma), inflammatory and autoimmune diseases(arthritis, Crohn's disease, graft versus host disease, systemicsclerosis and multiple sclerosis), neurological diseases (depression,anxiety, dementia, Alzheimer's disease, neurodegenerative diseases,spinal cord injury, traumatic brain injury, peripheral neuropathy andHuntington's disease), musculoskeletal diseases (muscular dystrophy andmuscular injury), fibrotic diseases (scar reduction, pulmonary fibrosis,liver fibrosis and cardiac fibrosis), dermal diseases (wound healing,radiation mitigation, dermal repair, scar reduction, and alopecia),ocular diseases (macular degeneration, corneal scarring, and diabeticretinopathy), liver diseases (non alcoholic hepatosteatosis, hepaticfibrosis, hepatobilliary disease, fatty liver disease, cirrhosis, andliver fibrosis), oncology and related diseases (cancer and supportivecare for oncology), gastrointestinal disease (stress ulcers and Crohn'sdisease), and bone marrow diseases (recovery from myelosuppression dueto radiation or chemotherapy, autologous transplant, radiationmitigation, engraftment of transplant, allogenic transplant,engraftment, hematopoiesis and bone marrow injury, and myelodysplasticsyndromes). It is to be understood that such combination therapyconstitutes a further aspect of the compositions and methods oftreatment provided herein.

1. Compositions for Oral or Mucocutaneous Administration

Oral pharmaceutical dosage forms are solid, gel or liquid. The soliddosage forms are tablets, capsules, granules, and bulk powders. Types oforal tablets include compressed, chewable lozenges and tablets that maybe enteric-coated, sugar-coated or film-coated. Capsules may be hard orsoft gelatin capsules, while granules and powders may be provided innon-effervescent or effervescent form with the combination of otheringredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms,preferably capsules, suppositories, rapid dissolving forms (e.g. films,and redi-tablets) or tablets. The tablets, pills, capsules, troches andthe like can contain any of the following ingredients, or compounds of asimilar nature: a binder; a diluent; a disintegrating agent; alubricant; a glidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water-soluble FD andC dyes, mixtures thereof, and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds, whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials, whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H₂ blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric-coated tablets, because of theenteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film-coated tablets are compressedtablets, which have been coated with a polymer or other suitablecoating. Multiple compressed tablets are compressed tablets made by morethan one compression cycle utilizing the pharmaceutically acceptablesubstances previously mentioned. Coloring agents may also be used in theabove dosage forms. Flavoring and sweetening agents are used incompressed tablets, sugar-coated, multiple compressed and chewabletablets. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic acids include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water-soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compounds,which produce a pleasant, taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603 (the relevant portions thereof are incorporated herein byreference). Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpoly-alkylene glycol, including, but not limited to,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer tothe approximate average molecular weight of the polyethylene glycol, andone or more antioxidants, such as butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

2. Injectables, Solutions and Emulsions

Parenteral administration generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol orethanol. In addition, if desired, the pharmaceutical compositions to beadministered may also contain minor amounts of non toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. Implantation of a slow release or sustained-releasesystem, such that a constant level of dosage is maintained (see, e.g.,U.S. Pat. No. 3,710,795) is also contemplated herein. Briefly, acompound provided herein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate-controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intradermal,intravenous, subcutaneous and intramuscular administrations.Preparations for parenteral administration include sterile solutionsready for injection, sterile dry soluble products, such as lyophilizedpowders, ready to be combined with a solvent just prior to use,including hypodermic tablets, sterile suspensions ready for injection,sterile dry insoluble products ready to be combined with a vehicle justprior to use and sterile emulsions. The solutions may be either aqueousor nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions includes EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

3. Lyophilized Powders

Formulations contemplated herein also include lyophilized powders, whichcan be reconstituted for administration as solutions, emulsions andother mixtures. They may also be reconstituted and formulated as solidsor gels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, ina suitable solvent. The solvent may contain an excipient, which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at,typically, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage (10-2,000 mg,preferably 100-500 mg) or multiple dosages of the compound forappropriate dosing. The lyophilized powder can be stored underappropriate conditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, preferably 5-35 mg, more preferably about9-30 mg of lyophilized powder, is added per mL of sterile water or othersuitable carrier. The precise amount depends upon the selected compound.Such amount can be empirically determined.

4. Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof may beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma or other pulmonaryconditions, the relevant portions thereof are incorporated herein byreference). These formulations for administration to the respiratorytract can be in the form of an aerosol or solution for a nebulizer, oras a microfine powder for insufflation, alone or in combination with aninert carrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH˜5-7, with appropriatesalts.

5. Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono-, di- andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. The typical weight of a rectalsuppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

6. Articles of Manufacture

The compounds or pharmaceutically acceptable derivatives thereof can bepackaged as articles of manufacture containing packaging material, acompound or pharmaceutically acceptable derivative thereof providedherein, which is used for treatment, prevention or amelioration of oneor more symptoms associated the diseases including but not limited tocardiovascular disease (myocardial infarction, congestive heart failure,diabetic cardiovascular disease, atrial fibrillation, hypertension,peripheral vascular disease, erectile dysfunction, stroke,pre-eclampsia, coated stents to inhibit restenosis, Marfan syndrome, andabdominal/thoracic aortic aneurysm), metabolic diseases (insulinresistance and metabolic syndrome), renal diseases (diabetic renaldisease, drug-induced renal failure, and chronic renal failure),pulmonary diseases (pulmonary fibrosis, acute lung injury, pulmonaryhypertension, and asthma), inflammatory and autoimmune diseases(arthritis, Crohn's disease, graft versus host disease, systemicsclerosis and multiple sclerosis), neurological diseases (depression,anxiety, dementia, Alzheimer's disease, neurodegenerative diseases,spinal cord injury, traumatic brain injury, peripheral neuropathy, andHuntington's disease), musculoskeletal diseases (muscular dystrophy andmuscular injury), fibrotic diseases (scar reduction, pulmonary fibrosis,liver fibrosis and cardiac fibrosis), dermal diseases (wound healing,radiation mitigation, dermal repair, scar reduction, and alopecia),ocular diseases (macular degeneration, corneal scarring, and diabeticretinopathy), liver diseases (non alcoholic hepatosteatosis, hepaticfibrosis, hepatobilliary disease, fatty liver disease, cirrhosis, andliver fibrosis), oncology and related diseases (cancer and supportivecare for oncology), gastrointestinal disease (stress ulcers and Crohn'sdisease), and bone marrow diseases (recovery from myelosuppression dueto radiation or chemotherapy, autologous transplant, radiationmitigation, engraftment of transplant, allogenic transplant,engraftment, hematopoiesis and bone marrow injury, and myelodysplasticsyndromes) and a label that indicates that the compound orpharmaceutically acceptable derivative thereof is used for treatment,prevention or amelioration of one or more symptoms associated with theaforementioned diseases.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252 (the relevant portions thereof areincorporated herein by reference). Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disorder associated with cardiovasculardisease (myocardial infarction, congestive heart failure, diabeticcardiovascular disease, atrial fibrillation, hypertension, peripheralvascular disease, erectile dysfunction, stroke, pre-eclampsia, coatedstents to inhibit restenosis, Marfan syndrome, and abdominal/thoracicaortic aneurysm), metabolic diseases (insulin resistance and metabolicsyndrome), renal diseases (diabetic renal disease, drug-induced renalfailure, and chronic renal failure), pulmonary diseases (pulmonaryfibrosis, acute lung injury, pulmonary hypertension, and asthma),inflammatory and autoimmune diseases (arthritis, Crohn's disease, graftversus host disease, systemic sclerosis and multiple sclerosis),neurological diseases (depression, anxiety, dementia, Alzheimer'sdisease, neurodegenerative diseases, spinal cord injury, traumatic braininjury, peripheral neuropathy, and Huntington's disease),musculoskeletal diseases (muscular dystrophy and muscular injury),fibrotic diseases (scar reduction, pulmonary fibrosis, liver fibrosisand cardiac fibrosis), dermal diseases (wound healing, radiationmitigation, dermal repair, scar reduction, and alopecia), oculardiseases (macular degeneration, corneal scarring, and diabeticretinopathy), liver diseases (non alcoholic hepatosteatosis, hepaticfibrosis, hepatobilliary disease, fatty liver disease, cirrhosis, andliver fibrosis), oncology and related diseases (cancer and supportivecare for oncology), gastrointestinal disease (stress ulcers and Crohn'sdisease), and bone marrow diseases (recovery from myelosuppression dueto radiation or chemotherapy, autologous transplant, radiationmitigation, engraftment of transplant, allogenic transplant,engraftment, hematopoiesis and bone marrow injury, and myelodysplasticsyndromes).

E. Methods of Use and Treatment Methods of the Compounds andCompositions

The provided compounds can act selectively at certain GPCR receptors andcan be used as selective agonists of these receptors.

Compounds provided by the invention act as small molecule modulators ofthe actions of angiotensin-related peptides. The provided compounds canact as agonists of the Mas receptor, otherwise known as the receptor ofthe Ang(1-7) peptide. As part of, or in addition to or instead of theiractions of the angiotensin receptors, the provided compounds can mimicthe endogenous actions of the Ang(1-7) peptide and benefit from all ofits beneficial activities and therapeutic actions.

In a preferred embodiment, the provided compounds may be used asselective agonists of the Mas receptor and do not act as agonists of theAngII receptor AT1R. In another preferred embodiment, the providedcompounds may be used as agonists of the Mas receptor and/or as agonistsof the AngII receptor AT2R, but do not act as agonists of the AngIIreceptor AT1R. In another preferred embodiment, the provided compoundsact as agonists of the Mas receptor and/or as agonists of the AngIIreceptor AT2R, but do not act as antagonists of the AngII receptor AT1R.

In one embodiment, the invention provides pharmaceutical compositionscontaining a provided compound of formula 1 or its salt thereof and anyacceptable carrier that are useful for therapeutic administration.

In another embodiment the invention provides a method of increasing NOproduction in a cell comprising contacting the cell with an effectiveamount of a compound according to formula 1 (or any formulas disclosedherein derived from formula 1, such as formulas 2-11) or salts thereof.

In another embodiment the invention provides a method of reducing bloodglucose in a patient in need thereof comprising, administering to thepatient in an effective amount of a compound according to formula 1 (orany formulas disclosed herein derived from formula 1, such as formulas2-11) or salts thereof.

In a preferred embodiment, the provided method is used in a patient thathas diabetes mellitus.

In another embodiment the invention provides a method for reducing fataccumulation in a patient in need thereof comprising, administering tothe patient in an effective amount of a compound according to formula 1(or any formulas disclosed herein derived from formula 1, such asformulas 2-11) or salts thereof.

In a preferred embodiment, the provided method is used in a patient thathas non-alcoholic steatohepatitis.

In another embodiment the invention provides a method of enhancing bonemarrow progenitor cell proliferation in a patient in need thereofcomprising administering to the patient an effective amount of acompound according to formula 1 (or any formulas disclosed hereinderived from from formula 1, such as formulas 2-11) or salts thereof.

In a preferred embodiment, the provided method is used in a patient thathas myelodysplastic syndrome.

In another embodiment the invention provides a method for treating apatient with cancer comprising, administering to the patient in aneffective amount of a compound according to formula 1 (or any formulasdisclosed herein derived from from formula 1, such as formulas 2-11) orsalts thereof.

In a preferred embodiment, the provided method is used in a patient thathas breast cancer.

In another embodiment the invention provides a method of treating anangiotensin-related disease or disorder comprising: administering to apatient in need thereof an effective amount of a provided compound aprovided compound of formula 1 (or any formulas disclosed herein derivedfrom from formula 1, such as formulas 2-11) or salts thereof, or apharmaceutical composition containing a provided compound, wherein theamount of compound is effective to ameliorate at least one symptomassociated with the disease or disorder, or to postpone or prevent theonset of at least one symptom of the disease.

In an exemplary embodiment, the invention provides compounds, methodsand compositions for the treatment of diseases mediated by angiotensinII acting on its receptor type I (AT1R) or via other pathways.Accordingly, in one aspect, the invention features methods andcompositions for modulating, ameliorating or treating diseases orconditions associated with the adverse actions of an angiotensin-relatedpeptide, such as angiotensin II.

In another embodiment, the invention provides a method for the use of aprovided compound a provided compound of formula 1 or its salt thereofand compositions for the treatment of diseases or disorders and relatedconditions mediated by the undesired actions of an angiotensin-relatedpeptide, such as angiotensin II. In another embodiment, the inventionprovides a method for the use of the provided compounds and compositionsfor the treatment of disorders mediated by reduced stem/progenitor cellactivity.

The invention provides small molecule non-peptidic compounds, as well asmethods and compositions for the treatment of angiotensin-relateddiseases and disorders, including but not limited to cardiovasculardisease (myocardial infarction, congestive heart failure, diabeticcardiovascular disease, atrial fibrillation, hypertension, peripheralvascular disease, erectile dysfunction, stroke, pre-eclampsia, coatedstents to inhibit restenosis, Marfan syndrome, and abdominal/thoracicaortic aneurysm), metabolic diseases (insulin resistance and metabolicsyndrome), renal diseases (diabetic renal disease, drug-induced renalfailure, and chronic renal failure), pulmonary diseases (pulmonaryfibrosis, acute lung injury, pulmonary hypertension, and asthma),inflammatory and autoimmune diseases (arthritis, Crohn's disease, graftversus host disease, systemic sclerosis and multiple sclerosis),neurological diseases (depression, anxiety, dementia, Alzheimer'sdisease, neurodegenerative diseases, spinal cord injury, traumatic braininjury, peripheral neuropathy and Huntington's disease), musculoskeletaldiseases (muscular dystrophy and muscular injury), fibrotic diseases(scar reduction, pulmonary fibrosis, liver fibrosis and cardiacfibrosis), dermal diseases (wound healing, radiation mitigation, dermalrepair, scar reduction, and alopecia), ocular diseases (maculardegeneration, corneal scarring, and diabetic retinopathy), liverdiseases (non alcoholic hepatosteatosis, hepatic fibrosis,hepatobilliary disease, fatty liver disease, cirrhosis, and liverfibrosis), oncology and related diseases (cancer and supportive care foroncology), gastrointestinal disease (stress ulcers and Crohn's disease),and bone marrow diseases (recovery from myelosuppression due toradiation or chemotherapy, autologous transplant, radiation mitigation,engraftment of transplant, allogenic transplant, engraftment,hematopoiesis and bone marrow injury, and myelodysplastic syndromes).

In a preferred embodiment, the invention provides compounds, methods andcompositions for the treatment of metabolic diseases or disorders andrelated conditions, such as diabetes mellitus, diabetes-relatedcardiovascular diorders, diabetes-related dermal ulcerations,diabetes-related hypertension, diabetic ophthalmic diseases, andobesity-related diseases or conditions.

In an exemplary embodiment, the provided compounds, methods andcompositions are used for the reduction in the consequences ofhyperglycemia in diabetic patients without the effects of hypoglycemia.

In other exemplary embodiments, the provided compounds and compositionscan be used to treat an angiotensin-related disease or disorder andrelated conditions, including: cardiovascular disease, renal disease,hematologic disease, fibrotic disease, liver disease,autoimmune/inflammatory disease, metabolic disease, pulmonary disease,diabetes, ophthalmic disease, neurologic disease, or cancer.

More particularly, the invention provides a method of using the providedcompounds and pharmaceutical compositions for the treatment of multipleangiotensin-related diseases or disorders.

In one exemplary embodiment, the invention provides methods andcompositions for the treatment of a known angiotensin-related disease.

In a preferred embodiment, the invention provides a method for thetreatment of diabetes, obesity or another disease of the metabolicsystem.

Preferred methods and compositions include pharmaceutical compositionsfor topical, parenteral and oral administration comprising of a providedcompound and derivatives or a pharmaceutically acceptable salt, and apharmaceutically acceptable carrier. The invention also provides amethod of use of the provided pharmaceutical compositions for thetreatment of angiotensin-related diseases and disorders.

In an exemplary embodiment, the invention provides methods andcompositions for the treatment of metabolic diseases and disorders,including diabetes and related conditions, upon oral, parenteral (e.g.subcutaneous, intrathecal, epidural, and intravenous) and topicaladministration, such as delivery to the skin, the eye, or the mucosa.

In another embodiment, the provided compounds, methods and compositionsare employed in oral, parenteral, or topical administration comprisingof a provided compound or a pharmaceutically acceptable salt, and apharmaceutically acceptable carrier.

The invention will be further described in the following examples, whichare illustrative only, and which are not intended to limit the scope ofthe invention described in the claims.

EXAMPLES Example 1. Structure-Based Design and Identification ofNon-Peptidic Small Molecules that Selectively Bind to the Mas Receptor

The provided compounds were designed to have beneficial agonist activityat the Mas receptor, without adverse agonist activity at the AT1receptor. Since there are no available X-ray crystal structures for therelevant angiotensin receptors, such as the AT1, AT2 and Mas receptors,the provided compounds were defined by using GPCR homology modeling toevaluate key structural features. Homology models of these receptorswere generated using the Prime (Prime, v3.1, Schrödinger, LLC, New York,N.Y.) homology workflow. The sequence of AT1, AT2, and MAS weredownloaded from Universal Protein Resource (UniProt). The sequence forthe AT2R and MAS receptor was aligned with the sequence of thenociceptin/orphanin FQ receptor (PDB ID: 4EA3 Chain A) in the Primehomology workflow placing gaps in the loops regions. Prime was used toconstruct a homology model using a knowledge-based building method. Theextracellular loops of the output homology structure were deleted in theMaestro workspace and Schrodinger's Protein Preparation Wizard tool wasused to add hydrogens, correct bond orders, delete non-essential waters,predict side-chain protonation states, tautomers, and polar hydrogenorientations, and minimize the energy of the protein structure. Theorthosteric site of the homology model was analyzed for polar residuescapable of hydrogen bonding with the molecules.

Using these homology models, several exemplary series of compounds weremodeled, optimized, prepared, and evaluated in binding displacementassays with Ang II and Ang(1-7), as well in other related assays. Thesestudies resulted in the identification and validation of the keyrelevant structural features of the provided compounds.

A representative example involving a model related to the exemplarycompound 7 is provided in FIG. 2. For clarity, these models show only anethyl group in place of the butyl group of compound 7. In this example,the binding preference of compound 7 (FIG. 2A-D) at the AT2R is comparedwith the pyrazole isomer of compound 7 (FIG. 2E). Despite their smalldifference in structure, their binding orientation is significantlyaltered pointing to the importance of the more basic nitrogen atom incompound 7. In another comparison of compound 7 with the correspondingcompound where the pyridine ring is replaced with a benzene ring (FIG.2F-H), indicated that the presence of a basic nitrogen in compound 7,which is presumably protonated, prevents this compound from insertingitself into the non-polar environment of the sub-surface portion ofthese GPCRs, which is preferrd by the diphenyl structure (FIG. 2G-H).Instead, compound 7 is able to bind via an alternative orientationcloser to the surface (FIG. 2B-D). An alterantive preference exists forthe closely related compound where the pyridine ring is replaced with abenzene ring (FIG. 2F-H). The overall orientation of the bound compounds(FIGS. 2B vs 2G and 2D vs 2H), as well as the contact residues at thebinding site of the transmembrane GPCRs (FIGS. 2C vs 2E and 2F), aredramatically altered with the presence of the basic nitrogen present incompounds such as 7, enabling these compounds to differentially bind toAT2R. The binding of these compounds to AT1R and the Mas receptor hasanalogous differences, resulting in differentiated activity profiles.

Overall, these models reveal key structural features required by theprovided compounds to function as selective agonists of Mas, withoutsignificant agonist or antagonist activity of AT1R or AT2R. By adoptingthese differentiated binding preferences, the provided compounds are notable to properly bind to AT1R and AT2R, and they are expected to beunable to behave as effective agonists or antagonists of thesereceptors.

A representative example involving a model related to the postulatedbinding of exemplary compound 7 to the Mas receptor is provided in FIG.3. For clarity, these models show only an ethyl group in place of thebutyl group of compound 7. The postulated binding preference of compound7 at a homology model of the Mas receptor revealed several strongbinding interactions with polar residues at the binding site (FIG. 3B).The presence of a basic nitrogen, which is presumably protonated, aswell as the other polar groups in compound 7 enables this compound tointeract strongly at this polar site of the Mas Receptor. The contactresidues at the binding site (FIG. 3A), and the overall orientation ofthe bound compound closer to the surface of the Mas receptor (FIG. 3C,D)point to the unique binding profile of the provided compounds thatenables their ability to act as selective Mas receptor agonists. Incontrast, similar compounds without such features are expected to actmore differentially at the AT1R and/or AT2R without significant agonistactivity at the Mas receptor.

These binding motifs that prevent effective binding to AT1R and AT2R,but at the same time enable effective selective binding to the Masreceptor are not known in the art, and provide strong support for thestructural novelty of the provided exemplary compounds, which is alsoreflected in the corresponding exemplary binding data and the otherexemplary biological data provided herein.

Example 2. Synthesis of Exemplary Compound 7 (butyl(2-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethoxy)phenyl)sulfonylcarbamate)

In the following synthetic examples, efforts have been made to ensureaccuracy with respect to numbers used (e.g. amounts, temperature, etc.)but some experimental errors and deviations should be accounted for.Unless indicated otherwise, parts are parts by weight, molecular weightis weight average molecular weight, temperature is in degreescentigrade, and pressure is at or near atmospheric. Starting materialsused in these examples are generally either commercially available orcan be readily prepared from commercially available reagents by aprocedure involving one or more steps.

Step 1: Synthesis of 5-((1H-imidazol-1-yl)methyl)-2-bromopyridine. Thestarting material 2-bromo-5-(bromomethyl)pyridine was synthesizedaccording to a published protocol (Tetr. Lett. 2002, 43, 1697). To astirring solution of this compound (2 g, 8 mmol) in 20 mL of DMF wasadded imidazole (537 mg, 8 mmol, 1 eq) and K₂CO₃ (3.32 g, 24 mmol, 3 eq)and stirred overnight. The reaction was concentrated in vacuo. The crudemixture was dissolved in EtOAc and 10 mL of 10% citric acid andextracted. The organic layer was washed with H₂O then brine, dried withMgSO₄, concentrated in vacuo, and purified by automated chromatographyto yield 1.35 g of an off-white solid (71% yield, R_(f)=0.30 in 10% MeOHin DCM). ¹H NMR (400 MHz, CDCN) d 8.26 (d, J=2.4 Hz, 1H), 7.61 (s, 1H),7.51 (d, J=8.2 Hz, 1H), 7.45 (dd, J=8.3, 2.5 Hz, 1H), 7.04 (s, 1H), 6.97(s, 1H), 5.15 (s, 2H).

Step 2: Synthesis ofN-(tert-butyl)-4-(trifluoromethoxy)benzenesulfonamide. To a 500 mL roundbottom flask equipped with a stirbar was added4-(trifluoromethoxy)benzene-1-sulfonyl chloride, (25 g, 95.9 mmol) and100 mL of THF and the flask was cooled to 0° C. Tert-butylamine (100 mL,959 mmol, 10 eq) was dissolved in 100 mL of THF in an Erlenmeyer flask.The first 50 mL of the tert-butylamine solution was added dropwise tothe sulfonyl chloride solution with the remaining poured directly fromthe Erlenmeyer Flask. After the reaction was stirred for 2 hours in theice bath, the bath was removed and the reaction stirred at roomtemperature for 1 hour. The reaction was concentrated under vacuum toyield a white solid which was dissolved in H₂O and EtOAc, placed in aseparatory funnel, and extracted. The organic layer was washed with H₂O,a 10% aqueous solution of HCl, saturated NaHCO₃ solution, brine, driedwith MgSO₄, filtered through cotton, and concentrated in vacuo to yield28.26 g (quantitative) of a yellow oil which solidified under vacuumedstirring to a yellow crystalline solid. ¹H NMR (400 MHz, CDCl₃) d 7.90(d, J=8.8 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 5.32 (s, 1H), 1.15 (s, 9H).¹³C NMR (101 MHz, CDCl₃) d 151.80 (q, J=1.8 Hz), 142.04, 129.12, 120.87(d, J=1.0 Hz), 120.35 (q, J=259.1 Hz), 55.01, 30.15. ¹⁹F NMR (376 MHz,CDCl₃) d −57.87.

Step 3: Synthesis of (2-(N-(tert-butyl)sulfamoyl)-5-(trifluoromethoxy)phenyl)boronic acid.N-(tert-butyl)-4-(trifluoromethoxy)benzenesulfonamide (28.26 g, 95 mmol)was placed in a 500 mL round bottom flask equipped with a stir bar andplaced under high vacuum with stirring. A solid yellow crystalline solidformed which was broken up with a large NMR tube and placed underadditional high vacuum. 300 mL of DriSolv® THF was cannulated into theflask. The pressure was equilibrated with an argon balloon and the flaskwas cooled to ˜−78° C. in an acetone and dry ice bath. 2.5 M n-butyllithium (114 mL, 285 mmol, 3 eq) was added drop wise to the flask whilemaintaining the acetone and dry ice bath. The flask was quicklytransferred to an acetonitrile and dry ice bath and stirred for 3.5hours. (Place the reaction in the crushed dry ice then add theacetonitrile). The reaction was then cooled to ˜−78° C. in an acetoneand dry ice bath and triisopropyl borate (33 mL, 142.5 mmol, 1.5 eq)slowly at first then quickly. The reaction was stirred over nightwithout the addition of any more dry ice. The flask was opened and 200mL of 2N HCl was quickly added. The reaction mixture was extracted andthe aqueous was extracted with EtOAc and combined with the reactionorganic layer, dried with MgSO₄, filtered through cotton, andconcentrated in vacuo to yield 48.26 g of a crude yellow oil which wascarried on to the next step without further purification.

Step 4: Synthesis of2-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-N-(tert-butyl)-4-(trifluoromethoxy)benzenesulfonamide. The bromide product of Step 1 (1.35 g, 5.6 mmol) andthe boronic acid product from Step 3 (7.6 g, 22.4 mmol, 4 eq) werecombined in a 200 mL round bottom flask. Pd(PPh₃)₄ (1.3 g, 0.2 mmol,1.12) was added to the flask under an atmosphere of N₂, the flask wasplaced under high vacuum, and 60 mL of toluene, 10 mL of EtOH, and 33 mLof a 1M aqueous NaOH. The reaction was stirred at 85° C. overnight andconcentrated in vacuo. The residue was dissolved in EtOAc, extractedwith brine, the organic layer was dried with MgSO₄, filtered throughcotton, concentrated onto Celite®, and purified by automatedchromatography to yield 670 mg (26% yield). ¹H NMR (400 MHz, CD₃OD) d8.61 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.68 (d,J=7.9 Hz, 1H), 7.56 (df, J=8.8, 2.4, 1.1 Hz, 1H), 7.45 (d, J=2.0 Hz,1H), 5.42 (s, 2H), 1.22 (s, 9H). ¹³C NMR (101 MHz, CD₃OD) d 156.32,151.07, 147.22, 140.70, 140.47, 136.58, 132.95, 130.94, 124.91, 123.91,120.29 (q, J=257.6 Hz), 120.15, 54.33, 28.92. ¹⁹F NMR (376 MHz, CD₃OD) d−59.36. MS (ESI): m/z=455.0 [M+H]⁺.

Step 5: Synthesis of2-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethoxy)benzenesulfonamide.The product of Step 4 (670 mg, 1.47 mmol) was refluxed overnight in 3 mLof TFA. The reaction was cooled to room temperature, neutralized with asaturated NaHCO₃ solution, extracted with EtOAc, dried with MgSO₄,filtered through cotton, dried on Celite®, and purified by automatedchromatography with a 0% to 8% gradient of MeOH in DCM to yield 271 mgof the desired product (46% yield). ¹H NMR (400 MHz, CD₃OD) d 8.59 (s,1H), 8.25 (d, J=8.7 Hz, 1H), 7.85 (s, 1H), 7.79 (dd, J=8.0, 1.5 Hz, 1H),7.62 (d, J=8.1 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.47 (s, 1H), 7.23 (s,1H), 7.06 (s, 1H), 5.37 (s, 2H). ¹³C NMR (101 MHz, CD₃OD) d 157.93,152.57, 152.55, 148.69, 141.91, 141.50, 138.13, 134.20, 131.89, 125.63,125.14, 121.71 (q, J=515.7, 257.8 Hz), 121.66, 48.66. ¹⁹F NMR (376 MHz,CD₃OD) d −59.28. MS (ESI): m/z=399.0 [M+H]⁺.

Step 6: Synthesis of butyl(2-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethoxy)phenyl)sulfonylcarbamate.To a stirring solution of the product from Step 5 (271 mg, 0.68 mmol)and 4-(dimethylamino)pyridine (91 mg, 0.75 mmol, 1.1 eq) in 10 mL ofpyridine was added butyl chloroformate (1.76 mL, 13.6 mmol, 20 eq). Thereaction was stirred at room temperature overnight, and concentrated invacuo. The residue was dissolved in 20 mL of a 10% citric acid solutionand EtOAc. The organic layer was extracted three times with EtOAc anddried with MgSO₄, filtered through cotton, concentrated onto Celite®,and purified by automated chromatography with a 0% to 20% gradient ofMeOH in DCM to yield 289 mg of a white foam (58% yield). ¹H NMR (400MHz, CD₃OD) d 8.60 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.84 (d, J=7.4 Hz,1H), 7.71 (d, J=8.0 Hz, 1H), 7.62-7.53 (m, 1H), 7.46 (s, 1H), 7.36 (d,J=1.6 Hz, 1H), 7.30 (s, 1H), 5.49 (s, 2H), 3.98 (t, J=6.5 Hz, 2H),1.58-1.44 (m, 2H), 1.30 (dt, J=15.2, 7.3 Hz, 3H), 0.98-0.83 (m, 3H). ¹⁹FNMR (376 MHz, CDCl₃) d −55.37. MS (ESI): m/z=499.0 [M+H]⁺.

Example 3. Synthesis of Exemplary Compound 8 (butyl(2-(5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethoxy)phenyl)sulfonylcarbamate)

Step 1: Synthesis of 5((1H-imidazol-1-yl)methyl)-2-bromopyridine. Thestarting material 2-bromo-5-(bromomethyl)pyridine was synthesizedaccording to a published protocol (Tetr. Lett. 2002, 43, 1697). To a 50mL round bottom flask containing 1-methyl-2-imidazolidinone (250 mg, 2.5mmol) and NaH 60% dispersion in mineral oil (110 mg, 2.75 mmol, 1.1 eq)at 0° C. was added 3 mL of DriSolv® DMF. The reaction turned into acloudy white solid, then warmed to room temperature, and stirred for anhour. 2-bromo-5-(bromomethyl)pyridine (750 mg, 1.2 mmol, 3 eq) wasdissolved in 1 mL of DriSolv® DMF and the reaction was stirred overnightat room temperature. The reaction was concentrated in vacuo, dissolvedin EtOAc and a saturated solution of NH₄Cl, and extracted. The organiclayer was concentrated in vacuo, and purified by automatedchromatography to yield 173 mg (26%) of a light brown oil R_(f)=0.15 in75% EtOAc in hexanes/1% MeOH). ¹H NMR (600 MHz, CD₃OD) d 8.26 (d, J=2.4Hz, 1H), 7.62 (dd, J=8.2, 2.5 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 4.33 (s,2H), 3.36-3.31 (m, 2H), 3.28-3.23 (m, 2H), 2.77 (s, 3H). ¹³C NMR (151MHz, CD₃OD) d 150.70, 141.72, 140.28, 134.46, 129.45, 45.97, 45.95,43.46, 31.40.

Step 2: Synthesis ofN-(tert-butyl)-2-(5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethoxy)benzenesulfonamide.The bromide product of Step 1 (173 mg, 0.64 mmol) and the boronic acidproduct from Step 2 of Example 2 (874 mg, 2.54 mmol, 4 eq) were combinedin a round bottom flask. Pd(PPh₃)₄ (462 mg, 0.4 mmol, 0.63 eq) was addedto the flask under an atmosphere of N₂, the flask was placed under highvacuum, and 20 mL of toluene, 5 mL of EtOH, and 3.84 mL of a 1N aqueousNaOH. The reaction was stirred at 90° C. for 2 days, concentrated invacuo, dissolved in EtOAc and H₂O, and extracted. The organic layer waswashed with brine, filtered through Celite®, concentrated onto Celite®,and purified by automated chromatography to yield 232 mg (75%) of a tanoil R_(f)=0.25 in 80% EtOAc in hexanes with 1% MeOH). ¹H NMR (400 MHz,CD₃OD) d 8.46 (d, J=2.4 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.74 (dd,J=8.2, 2.3 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.46-7.37 (m, 1H), 7.33 (d,J=2.6 Hz, 1H), 4.34 (s, 2H), 3.33-3.13 (m, 4H), 2.69 (s, 3H), 1.09 (s,9H). ¹⁹F NMR (376 MHz, CD₃OD) d −59.16. MS (ESI): m/z=487.0 [M+H]⁺.

Step 3: Synthesis of2-(5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)-pyridin-2-yl)-4-(trifluoromethoxy)benzenesulfonamide.The product of Step 2 (232 mg, 0.47 mmol) was stirred for 2 days at roomtemperature in 10 mL of TFA. The reaction was neutralized with asaturated NaHCO₃ solution, extracted with EtOAc, dried and purified byautomated chromatography with a 0% to 2.8% gradient of MeOH in DCM toyield 121.4 mg (60%) of an off-white powder. ¹H NMR (400 MHz, CD₃OD) d9.16 (d, J=2.2 Hz, 1H), 8.78 (d, J=8.7 Hz, 1H), 8.45 (dd, J=8.1, 2.2 Hz,1H), 8.20 (dd, J=8.1, 0.9 Hz, 1H), 8.12 (ddd, J=8.8, 2.5, 1.2 Hz, 1H),8.07 (d, J=2.5 Hz, 1H), 5.02 (s, 2H), 3.98-3.84 (m, 4H), 3.34 (s, 3H).¹⁹F NMR (376 MHz, CD₃OD) d −57.66.

Step 4: Synthesis of butyl((2-(5-((3-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethoxy)phenyl)sulfonyl)carbamate.Prepared similarly to Step 6 of Example 2. ¹H NMR (400 MHz, CD₃OD) d8.43 (dd, J=2.3, 0.9 Hz, 1H), 8.23 (d, J=8.9 Hz, 1H), 7.73 (dd, J=8.0,2.2 Hz, 1H), 7.54-7.44 (m, 2H), 7.30-7.24 (m, 1H), 4.37 (s, 2H), 3.92(t, J=6.5 Hz, 2H), 3.33-3.23 (m, 4H), 2.72 (s, 3H), 1.48-1.37 (m, 2H),1.26-1.15 (m, 2H), 0.80 (t, J=7.4 Hz, 3H). ¹⁹F NMR (376 MHz, CD₃OD) d−59.29. MS (ESI): m/z=531.0 [M+H]⁺.

Example 4. Synthesis of Compound 9 (butyl(2-(5-(morpholinomethyl)pyridin-2-yl)-4-(trifluoromethoxy)phenyl)sulfonyl-carbamate),and compound 10 (butyl (2-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethoxy) phenyl)sulfonylcarbamate)

Step 1: Synthesis ofN-(tert-butyl)-2-(5-methylpyridin-2-yl)-4-(trifluoromethoxy)benzenesulfonamide.2-Bromo-5-methylpyridine (1.23 mg, 7.15 mmol) and the boronic acidproduct from Step 2 of Example 2 (4.9 g, 14.3 mmol, 2 eq) were combinedin a round bottom flask. Pd(PPh₃)₄ (1.65 g, 1.43 mmol, 0.2 eq) was addedto the flask under an atmosphere of N₂, the flask was placed under highvacuum, and 100 mL of toluene, 20 mL of EtOAc, and 42 mL of a 1N aqueousNaOH. The reaction was stirred at 90° C. for 2 days, concentrated invacuo, dissolved in EtOAc and H₂O, and extracted. The organic layer waswashed with NaHCO₃, dried with MgSO₄, filtered, concentrated ontoCelite®, and purified by automated chromatography with a 5% to 40%gradient of EtOAc in hexanes to yield 3.027 g (R_(f)=0.3 in 20% EtOAc inhexanes). ¹H NMR (400 MHz, CDCl₃) δ 8.15 (dt, J=2.3, 0.8 Hz, 1H), 7.95(d, J=8.7 Hz, 1H), 7.69-7.64 (m, 1H), 7.38 (ddd, J=8.0, 2.3, 0.9 Hz,1H), 7.12 (dd, J=8.0, 0.8 Hz, 1H), 7.06 (ddd, J=8.7, 2.5, 1.2 Hz, 1H),2.08 (d, J=1.0 Hz, 3H), 1.04 (s, 9H). ¹⁹F NMR (376 MHz, CDCl₃) δ −57.76.MS (ESI): m/z: [M+H]⁺ calculated 389.11; found 389.0. MS (ESI):m/z=389.0 [M+H]⁺.

Step 2; Synthesis of2-(5-(bromomethyl)pyridin-2-yl)-N-(tert-butyl)-4-(trifluoromethoxy)benzenesulfonamide.A solution of the product of Step 1 (3.027 g, 7.8 mmol) andN-bromosuccinimide (1.526 g, 8.6 mmol, 1.1 eq) in 100 mL of DCM and 100mL of H₂O was stirred under UV irradiation at 80-90° C. in a roundbottom flask outfitted with a reflux condenser for 48 hours. Thereaction was then cooled to room temperature, poured into a separatoryfunnel, and extracted. The organic layers were dried with MgSO₄,filtered through cotton, concentrated onto Celite®, and flushed throughan silica gel column via automated chromatography with a 5% to 40%gradient of EtOAc in hexanes to yield 517 mg of a crude mixture that wascarried on to the next step without further purification. MS (ESI): m/z:466.9 [M+H]⁺.

Step 3; Synthesis ofN-(tert-butyl)-2-(5-(morpholinomethyl)pyridin-2-yl)-4-(trifluoromethoxy)benzenesulfonamide.To a stirring solution of the product of Step 2 (186 mg, 0.4 mmol) in 3mL of DMF was added morpholine (0.104 mL, 1.19 mmol, 3 eq) and K₂CO₃(329 mg, 2.39 mmol, 6 eq) and stirred at room temperature for 2 days.The reaction was concentrated in vacuo onto Celite and purified byautomated chromatography with a gradient 0% to 100% EtOAc in hexanes toyield 67 mg of a clear film (35% yield, R_(f)=0.3 in 50% EtOAc inhexanes). ¹H NMR (400 MHz, CD₃OD) d 8.63 (d, J=1.5 Hz, 1H), 8.27 (d,J=8.8 Hz, 1H), 7.97 (dd, J=8.1, 2.2 Hz, 1H), 7.67 (dd, J=8.0, 0.7 Hz,1H), 7.56 (ddd, J=8.8, 2.5, 1.2 Hz, 1H), 7.47 (dd, J=2.4, 0.7 Hz, 1H),3.78-3.70 (m, 4H), 3.66 (s, 2H), 2.59-2.50 (m, 4H), 1.25 (s, 9H). ¹⁹FNMR (376 MHz, CD₃OD) d −59.27. MS (ESI): m/z: 474.0 [M+H]⁺.

Step 4: Synthesis of butyl((2-(5-(morpholinomethyl)pyridin-2-yl)-4-(trifluoromethoxy)phenyl)sulfonyl)carbamate.The product of Step 3 (67 mg, 0.14 mmol) was stirred for 2 days at roomtemperature in 10 mL of TFA. The reaction was stirred at roomtemperature for 2 days, concentrated in vacuo, and dissolved in MeOH andconcentrated in vacuo 3 times. To the resulting crude product was added4-(dimethylamino)pyridine (48.8 mg, 0.4 mmol, 2.85 eq), butylchloroformate (0.361 mL, 2.8 mmol, 20 eq), and 5 mL of pyridine. Thereaction was stirred at room temperature for 2 days and concentrated invacuo. To the residue was 300 mg of citric acid then EtOAc and H₂O. Theorganic layer was extracted three times with EtOAc and dried with MgSO₄,filtered through cotton, concentrated onto Celite®, and purified byautomated chromatography to yield 44.5 mg the pure product (61% yield).¹H NMR (400 MHz, CD₃OD) d 8.57 (s, 1H), 8.31 (d, J=8.8 Hz, 1H), 7.90 (d,J=7.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.59-7.48 (m, 1H), 7.34 (d, J=2.6Hz, 1H), 3.92 (t, J=6.5 Hz, 2H), 3.81-3.71 (m, 4H), 2.71-2.61 (m, 4H),1.51 (dd, J=8.9, 5.8 Hz, 2H), 1.32 (dt, J=11.3, 3.7 Hz, 2H), 0.91 (t,J=7.3 Hz, 3H). ¹⁹F NMR (376 MHz, CD₃OD) d −59.27. MS (ESI): m/z: 518.0[M+H]⁺.

Step 5: Synthesis ofN-(tert-butyl)-2-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethoxy)benzenesulfonamide.To a stirring solution of the product of Step 2 (136 mg, 0.29 mmol) in 3mL of DMF was added 1-methylpiperazine (98.6 μL, 0.87 mmol, 3 eq) andK₂CO₃ (240 mg, 1.74 mmol, 6 eq) and stirred at room temperature for 2days. The reaction was concentrated in vacuo onto Celite and purified byautomated chromatography with a gradient 0% to 20% MeOH in DCM to yield41 mg of a clear film (29% yield, R_(f)=0.2 in 10% MeOH in DCM). ¹H NMR(400 MHz, CD₃OD) d 8.61 (d, J=1.6 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.95(dd, J=8.1, 2.2 Hz, 1H), 7.66 (dd, J=8.1, 0.6 Hz, 1H), 7.56 (ddd, J=8.8,2.5, 1.2 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 3.68 (s, 2H), 2.58 (s, 8H),2.34 (s, 3H), 1.24 (s, 9H). ¹⁹F NMR (376 MHz, CD₃OD) d −59.32. MS (ESI):m/z: 487.2 [M+H]⁺.

Step 6: Synthesis of butyl((2-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)-4-(trifluoromethoxy)phenyl)sulfonyl)carbamate.The product of Step 6 (41 mg, 0.07 mmol) was stirred for 2 days at roomtemperature in 4.5 mL of TFA. The reaction was stirred at roomtemperature for 2 days, concentrated in vacuo, and dissolved in MeOH andconcentrated in vacuo 2 times. To the resulting crude product was added4-(dimethylamino)pyridine (9 mg, 0.14 mmol, 1 eq), butyl chloroformate(0.191 mL, 1.48 mmol, 20 eq), and pyridine. The reaction was stirred atroom temperature for 2 days and concentrated in vacuo. To the residuewas 300 mg of citric acid then EtOAc and H₂O. The organic layer wasextracted three times with EtOAc and dried with MgSO₄, filtered throughcotton, concentrated onto Celite®, and purified by automatedchromatography to yield 44 mgs of an off-white foam (quantitative,R_(f)=0.1 in 20% MeOH in DCM). ¹H NMR (400 MHz, CD₃OD) d 8.58 (s, 1H),8.27 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 7.63-7.49 (m, 2H), 7.33 (d, J=3.1Hz, 1H), 3.97 (t, J=6.4 Hz, 2H), 3.75 (s, 2H), 2.81 (p, J=15.8, 15.2 Hz,19H), 1.47 (q, J=6.9 Hz, 2H), 1.27 (dq, J=14.8, 7.5, 6.8 Hz, 4H), 0.85(t, J=7.3 Hz, 3H). ¹⁹F NMR (376 MHz, CD₃OD) d −59.25. MS (ESI): m/z:531.1 [M+H]⁺.

Example 5. Synthesis of Exemplary Compound 11 (butyl(2-(5-((1H-imidazol-1-yl)methyl)thiazol-2-yl)-4-(trifluoromethoxy)phenyl)sulfonylcarbamate)

Step 1: Synthesis of 2-bromo-5-(bromomethyl)thiazole. A solution of2-bromo-5-methylthiazole (1 g, 5.6 mmol) and N-bromosuccinimide (1.1 g,6.18 mmol, 1.1 eq) in 40 mL of DCM and 40 mL of H₂O was stirred under UVirradiation at 90° C. in a round bottom flask outfitted with a refluxcondenser for 3 hours. The reaction was then cooled to room temperature,poured into a reparatory funnel, and extracted. The aqueous layer wasextracted twice more with DCM, the organic layers combined, dried withMgSO₄, filtered through cotton, concentrated and purified by automatedchromatography with a 0% to 3% gradient of EtOAc in hexanes to yield1.24 g (78%). ¹H NMR (400 MHz, CDCl₃) d 7.46 (d, J=0.9 Hz, 1H), 4.57 (d,J=0.9 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) d 141.92, 139.80, 137.39, 22.37.MS (ESI): m/z: 255.8 [M+H]⁺.

Step 2: Synthesis of 5-((1H-imidazol-1-yl)methyl)-2-bromothiazole. To astirring solution of the product of Step 1 (765 mg, 2.98 mmol) in 20 mLof DMSO was added imidazole (202 mg, 2.98 mmol, 1 eq) and K₂CO₃ (1.23 g,8.94 mmol, 3 eq) and stirred overnight. The reaction was extracted withbrine and EtOAc and concentrated in vacuo, and purified by automatedchromatography to yield 306.6 mg (42%) of the desired product. MS (ESI):m/z: 243.9 [M+H]⁺.

Step 3: Synthesis of2-(5-((1H-imidazol-1-yl)methyl)thiazol-2-yl)-N-(tert-butyl)-4-(trifluoromethoxy)benzenesulfonamide.The bromide product of Step 2 (306.6 mg, 1.26 mmol) and the boronic acidproduct from Step 2 of Example 2 (1.29 g, 3.78 mmol, 3 eq) were combinedin a round bottom flask. Pd(PPh₃)₄ (290 mg, 0.25 mmol, 0.2 eq) was addedto the flask under an atmosphere of N₂, the flask was placed under highvacuum, and 10 mL of toluene, 3 mL of EtOH, and 1.26 mL of a 2M aqueousNa₂CO₃. The reaction was stirred at 90° C. for 2 days, filtered throughCelite®, concentrated onto Celite®, and purified by automatedchromatography to yield 157 mg of a brown oil (27% yield, R_(f)=0.30 in5% MeOH in DCM).

Step 4: Synthesis of2-(5-((1H-imidazol-1-yl)methyl)thiazol-2-yl)-4-(trifluoromethoxy)benzenesulfonamide.The product of Step 3 (157 mg, 0.34 mmol) was stirred for 2 days at roomtemperature in 10 mL of TFA. The reaction was neutralized with asaturated NaHCO₃ solution, extracted with EtOAc, dried on Celite®, andpurified by automated chromatography with a 0% to 10% gradient of MeOHin DCM to yield 107 mg of an off-white powder (78% yield). MS (ESI):m/z: 404.9 [M+H]⁺.

Step 5: Synthesis of butyl((2-(5-((1H-imidazol-1-yl)methyl)thiazol-2-yl)-4-(trifluoromethoxy)phenyl)sulfonyl)carbamate.To a stirring solution of the product from Step 4 (64.6 mg, 0.16 mmol)and 4-(dimethylamino)pyridine (19.5 mg, 0.16 mmol, 1 eq) in 3 mL ofpyridine was added butyl chloroformate (0.407 mL, 3.2 mmol, 20 eq). Thereaction was stirred at room temperature for 2 days and concentrated invacuo. To the residue was 300 mg of citric acid then EtOAc and H₂O. Theorganic layer was extracted three times with EtOAc and dried with MgSO₄,filtered through cotton, concentrated onto Celite®, and purified byautomated chromatography with a 0% to 20% gradient of MeOH in DCM toyield 40.7 mg (50% yield). ¹H NMR (600 MHz, CD₃OD) d 8.46 (s, 1H), 8.22(d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.56-7.34 (m, 3H), 7.26 (s, 1H), 5.61(s, 2H), 3.84 (t, J=6.5 Hz, 2H), 1.46-1.32 (m, 2H), 1.25-1.09 (m, 2H),0.76 (t, J=7.4 Hz, 3H). ¹⁹F NMR (564 MHz, CD₃OD) d −59.35. MS (ESI):m/z=504.9 [M+H]⁺ MS (ESI): m/z: 505.0 [M+H]⁺.

Example 6. Inability of Exemplary Compound 7 to Compete with Ang II onAngiotensin Receptors AT1R and AT2R

Compound 7 was evaluated in vitro for its ability to compete withratholabeled Ang II or analogs in a displacement assay for AT1R and AT2Rreceptors. The results, showed that compound 7 had very weak activity atthe AT1 receptor, displacing Ang II with an EC50 greater than 10 μM,suggesting that compound 7 is not an effective agonist or antagonist ofAT1R. In the same AT1R assay, a compound similar to 7, wherein thepyridine ring was replaced by a benzene ring had a similar activity,replacing Ang II with an EC50 greater than 10 μM. In the AT2Rdisplacement assay compound 7 displaced Ang II with an EC50 greater than10 μM, suggesting that it is not an effective agonist or antagonist ofAT2R. In the same AT2R assay, a compound similar to 7, wherein thepyridine ring was replaced by a benzene ring was able to replace Ang IIwith an EC50 lower than 0.5 μM.

These results point to the inherent selectivity of exemplary compound 7and indicate that compound 7 at sub-micromolar concentrations does notbind effectively to either AT1R or AT2R and therefore is not aneffective agonist or antagonist of these receptors. These results alsoindicate that the overall design of exemplary compound 7 does not allowcompounds of this type to effectively bind to AT1R, while the presenceof a basic nitrogen in the middle aromatic ring (e.g. pyridine)significantly reduces the ability of the compound to bind to AT2R.

Example 7. Activity of Exemplary Compounds 7, 8, 9, 10, and 11 in aCompetition Binding Assay Involving the Displacent of FluorescentAng(1-7)

CHO cells stably transfected with recombinant Human mas1 proto-oncogendriven by the human cytomegalovirus were grown to 80% confluency. Thecells were detached with trypsin and harvested by centrifugation. Cellswere washed three times in progressively colder buffers. The finalnumber of cells per assay was 5×10⁵. All subsequent steps were performedon ice. Test compound was added to the cells for 10 minutes prior toaddition of fluorescently labeled A(1-7). After 10 minutes furtherincubation, the cells were washed to remove unbound A(1-7) and thefluorescence bound was read at an excitation of 490 nm and an emissionof 520 nm.

In this binding assay, exemplary compounds 7, 8, 9, 10, and 11 were ableto displace fluorescent Ang(1-7) as follows:

Compound % Displacement Compound 7 28.1% Compound 8 18.6% Compound 917.3% Compound 10 22.0% Compound 11 23.0%

These results indicate that exemplary compounds 7, 8, 9, 10, and 11 areable to effectively displace Ang(1-7) from Mas receptor with variableefficiency, suggesting that the provided compounds behave as mimics ofAng(1-7) that is able to bind onto Mas receptor. Taken together, theresults from Examples 6 and 7, indicate that the provided compounds areable to selectively bind to the receptor of Ang(1-7) but not to thereceptors of Ang II, i.e. AT1R or AT2R.

Example 8. Activity of Exemplary Compound 7 Involving the Mas Receptor

Transfected cells that express Mas were used to identify and evaluateprovided compounds as Mas agonists, by promoting NO production asreadouts. CHO cells stably transfected with pTEJ-8 vector containingrecombinant Human Mas1 clone were grown to confluency. Cells were washedthree times for 30/5/5 minutes with prewarmed (37° C.) Tyrodes Salts(supplemented with 1 g/L NaHCO₃, and 1.9 g/L d-Glucose). Cells wereincubated for a short time in 700 μL of supplemented Tyrodes saltscontaining 10 μM PTIO, 100 μM DAN, and 1 mM L-arginine. When usingantagonist for competition assays, cells were exposed to the inhibitorat 1×10⁻⁷ M for 15 minutes, before additional drugs are added.

Chemicals (10⁻⁸ to 10⁻⁶ M or the maximum concentration found not tocause cytotoxicity) to be screened were added to the cell medium and theplates were agitated for 1 minute before being placed into the incubatorfor 2 hours. After 2 hours, cellular supernatants were transferred toopaque 96 well plates, and the fluorescence intensity was recorded at anex/em of 380/425.

Compound 7 was found to be a potent and selective agonist of Mas, whereits ability to enhance NO production was shown to be similar to that ofA(1-7) (FIG. 4). In this assay, the EC50 was found to be 10 nM. Toconfirm that Compound 7 is a selective Mas agonist, co-administration ofA779, a selective Mas antagonist, was able to reduce NO production backto baseline.

Example 9. Activity of Exemplary Compound 7 Reduces Blood Glucose inDiabetes

Mice homozygous for the diabetes spontaneous mutation Lepr^(db)(BKS.Cg-Dock7^(m)+/+Lepr^(db)/J), which is an obese model of type 2diabetes as a consequence of truncation of the leptin receptor, haveverified plasma glucose levels >500 mg/dL prior to initiation oftreatment. Food and water were available ad libitum, and all mice werekept on a 12-hour light/dark cycle. BKS.Cg-Dock7^(m)+/+Lepr^(db)/J miceand their heterozygous controls (n=6/group) were administered eithersaline (control), Ang-(1-7) (500 mcg/kg/day), or Compound 7 500mcg/kg/day for two weeks by subcutaneous (SC) injection. Mice werefasted overnight prior to assessment of plasma glucose levels. Blood wastaken from the saphenous vein and tested for glucose levels by aglucometer.

In this model, Compound 7 treated group revealed that fasting bloodglucose (FBG) measured at the end of the study was significantly lower(p<0.05) than db/db mice treated with saline (FIG. 5). The glucose ofCompound 7 treated mice were statistically significantly lower thaneither db/db controls or db/db-treated with Ang(1-7). Compound 7 wasable to reduce peripheral glucose >40% of levels found in vehicle orA(1-7) treated mice. In terms of the excess blood glucose overnon-diabetic controls, Compound 7 was able to reduce FBG by 72%.

Example 10: Activity of Exemplary Compound 7 Involving PreventingOrganmegaly in Diabetes and Metabolic Syndrome

Compound 7 (500 mcg/kg/day) or Ang(1-7) (500 mcg/kg/day) treated db/dbmice were euphanized after 14 days of treatment. At necropsy, organswere collected for histology and weights. In FIG. 6A to 6C, hearts, leftand right kidney normalized to tibia length were weight where db/dbtreated with Compound 7 were lower than db/db-controls (saline) anddb/db treated with Ang(1-7). In this model, Compound 7 prevented thedevelopment of cardiomegaly (A) and left kidney hypertrophy (B), wherethe difference between db/db controls was statistically significant(p<0.05).

Example 11: Activity of Exemplary Compound 7 is Able to Prevent FatAccumulation in the Liver of Diabetic Mice

The lipid levels found in the liver was evaluated in db/db animalstreated for 14 days with vehicle, 500 mcg/kg/day Ang(1-7) or Compound 7.Livers isolated from mice were harvested. Liver tissue sections werewashed with cold saline and frozen in the presence of optimum cuttingtemperature (OCT) formulation. Tissues were then cut into 10-μm sectionsusing a cryostat. Oil Red O staining and H&E staining were performedaccording to published procedures (Yang et al., 2013). The tissues wereobserved and images acquired using a light microscope (Olympus BX51)(FIG. 6). Compound 7 (FIG. 6 right panel) reduced Oil Red staining (reddroplets reflect lipid deposition) compared with db/db controls (FIG. 6left panel).

Example 12: Activity of Exemplary Compound 7 is Able to Enhance BoneMarrow Progenitor Cells Proliferation

The femurs and tibia were collected from db/db mice treated 500mcg/kg/day Ang(1-7) or Compound 7 subcutaneously for 14 days wereeuphanized and the bone marrow were collected by flushing with PBScontaining 2% fetal calf serum. After collection of the bone marrow, thered blood cells will be lysed with a hypotonic solution (describedabove), mixed with 0.04% trypan blue and the number of nucleated cellswas assessed by hematocytometer under light microscopy. Aliquots ofcells were then resuspended at 1×10⁶ cells/ml (GM and GEMM, bonemarrow), 1.5×10⁶ cells/ml (BFU-E, bone marrow). One hundred μ1 of eachsuspension was added to 900 μl of semisolid medium containing 0.9%methyl cellulose in Iscove's MDM, 15% fetal calf serum, 1% bovine serumalbumin, 10 μg/ml bovine pancreatic insulin, 200 μg/ml humantransferrin, 10⁻⁴ M 2-mercaptoethanol, 2 mM glutamine, 10 ng/mlrecombinant murine interleukin 3, 10 ng/ml recombinant human interleukin6, 50 ng/ml recombinant murine stem cell factor and 3 units/mlerthropoietin. This mixture was then added to duplicate wells of a 24well plate. The cultures were then placed at 37° C. in a humidifiedatmosphere of 5% CO₂ in air. At day 14, the number of progenitorcolonies formed was enumerated under phase contrast microscopy.

The bone marrow cells were also cultured to assess the number of MSCs bya CFU—F assay. 2.5×10⁵ cells/ml, 2 ml per well, were diluted intoMesencult medium (Stem Cell Technologies, Vancouver, BC, Canada) and 2mL were placed in each well of a 24 well plate. The cultures were thenincubated at 37° C. in a humidified atmosphere of 5% CO₂ in air. At days2, 5 and 8, the number of progenitor colonies formed was enumeratedunder phase contrast microscopy.

Diabetes causes a reduction in the health of the bone marrow, the sourceof a number of progenitors that participate in healing, particularlyblood cells (red cells, platelets and leukocytes). Treatment with bothAng(1-7) and Compound 7 was able to increase bone marrow counts.Compound 7 was comparable to Ang(1-7) with regards to increasing in bonemarrow cell number as well as early progenitors (CFU-GEMM), myeloidprogenitors (CFU-GM), erythroid progenitors (BFU-E) and mesenchymal stemcells (MSC) (FIG. 8).

Example 13. Activity of Exemplary Compound 7 in Antitumor Activity

Compound 7 was evaluated for its ability to modulate cancerproliferation using MDA MB 231 breast cancer cell line. MDA MB 231 wastreated with increasing concentration of Compound 7 ranged from 1×10⁻¹²to 1×10⁻³ M, where the cells were incubated for 48 hours. After theincubation, cellular viability was evaluated using3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT,where viable cells are able to reduce MTT to formazan and form aninsoluble crystal. The solubilized crystal can be spectrometricallydetermine, where cellular viability is compared to cells treated withvehicle. The cellular viability of MDA MB 231 is summarized (FIG. 9).The addition of Compound 7, a potential Mas agonist, did not increasebreast cancer cell proliferation and thus does not enhance tumorproliferation. Rather at 1×10⁻¹² M (1 pmole) of Compound 7, the cellularproliferation was only 70% of vehicle treated. Additionally, MDA MB 231viability decreased in a concentration dependent manner, where the IC50was established at 5.82×10⁻⁸M (58 μM) when using a Hill-slope analysis.

Example 14

Compound 7 was evaluated for oral bioavailability at 500 μg/kg inC57Bl/6 mice. The drug was given by intravenous injection or by oralgavage and blood was collected at 0.5, 1, 2, 4, 8, 24 hours intoheparinized tubes. The level of drug in the blood was measured by liquidchromatograph-mass spectrometry. Bioavailability was determined usingthe following ratio AUC_(IG)/AUC_(IV) (FIG. 10). These pharmacokineticsstudies showed that Compound 7 has a 30% bioavailability after oralgavage and can be formulated to further enhance its bioavailability.

Example 15

Compound 7 was evaluated for acute toxicity at 500 μg/kg in C57Bl/6 micethat was given as either a subcutaneous or intravenous injection, andits safety was evaluated for 7 days after treatment. No overt signs oftoxicity, no gross lesions or changes in organ weight or hematology wereseen in this range finding study

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1. A method for treating an angiotensin-related disease or disorder; postponing or preventing the onset of a symptom of an angiotensin-related disease or disorder; reducing blood glucose; preventing organmegaly; or enhancing bone marrow progenitor cell proliferation in a patient in need thereof, comprising administering to the patient an effective amount of a compound having the general formula 1:

wherein: ring A is a five-membered or six-membered heteroaryl or heterocyclyl ring containing either a combination of two non-adjacent nitrogen or oxygen atoms, or a combination of three or four nitrogen or oxygen atoms; ring B is a five-membered or six-membered heteroaryl ring that contains at least one nitrogen atom; A¹, A², A³, A⁴ are independently selected from a group consisting of ═N—, —C(═O)—, —C(R^(a))═, ═C(R^(b))—, —C(R^(c))(R^(d))—N(R^(e))—, —C(R^(c))(R^(d))—O—, and —[C(R^(c))(R^(d))]_(n)—, wherein n is 1 or 2; X¹—X² is —(R⁶)C—N—, —N—C(R⁶)—, —N—N—, —N—O—, —O—N—, —N—S— or —S—N—; X³ is —(R^(c))C═C(R⁸)—, —O—, —S—, or —N(R⁹)—; Z is —O—, —NH— or a bond to R⁵; R^(a) and R^(b) are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy, or R^(a) and R^(b), together with the atoms to which they are attached, form a ring of up to 6 atoms; R^(c) and R^(d) are independently selected from a group consisting of hydrogen, alkyl, aryl, and heteroaryl, or R^(c) and R^(d), together with the atoms to which they are attached, form a ring of up to 6 atoms; R^(e) is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; R¹, R³, R⁴, R⁶, R⁷, and R⁸ are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, and aryloxyalkyl; R² is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; R⁵ is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, or aryloxyalkyl; and R⁹ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; or a pharmaceutically acceptable salt thereof, to treat the angiotensin-related disease or disorder; to postpone or prevent the onset of a symptom of an angiotensin-related disease or disorder; to reduce blood glucose; to prevent organmegaly; or to enhance bone marrow progenitor cell proliferation.
 2. The method of claim 1, ring A is selected from a group consisting of:

wherein: R¹⁰ and R¹¹ are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy, or R¹⁰ and R¹¹, together with ring A to which they are attached, form:

wherein R^(f), R^(g), R^(h), and R^(i), are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, and aryloxyalkyl; R¹² is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido; R¹³ is hydrogen, alkyl, aryl or heteroaryl; R¹⁴ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and ring B is selected from a group consisting of:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1, wherein the compound has a general formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1, wherein the compound has general formula of 2a, 2b, 3a or 3b:

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1, wherein the compound has general formula of 4a, 4b, 5a, 5b, 6a or 6b:

wherein R¹⁵ is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl or pentafluoroethyl; and R¹⁶ is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino; or a pharmaceutically acceptable salt thereof.
 6. The method of claim 3, wherein R¹⁰, R¹¹ and R¹² are hydrogen, or R¹⁵ is trifluoromethyl, or R¹⁶ is ethyl, or Z is selected from the group consisting of —O— and —NH—.
 7. The method of claim 1, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 8. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 10. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 11. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 12. The method of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 13. The method of claim 1, wherein the angiotensin-related disease or disorder is a cardiovascular disease, a metabolic disease, a renal disease, an inflammatory/autoimmune disease, an ophthalmic disease, a pulmonary disease, a gastrointestinal disease, a neurological disease, or a bone marrow disease.
 14. The method of claim 1, wherein the angiotensin-related disease or disorder is a metabolic disease or disorder or a condition related thereto, diabetes mellitus, a diabetes-related cardiovascular disorder, a diabetes-related dermal ulceration, diabetes-related hypertension, a diabetes-related ophthalmic disease, or an obesity-related disease or conditions.
 15. The method of claim 1, the disease is diabetes mellitus.
 16. The method of claim 1, wherein the disease is myelodysplastic syndrome.
 17. The method of claim 1, the disease is diabetic ophthalmic disease.
 18. The method of claim 1, wherein the method is for reducing blood glucose in a patient.
 19. The method of claim 1, wherein the patient has diabetes mellitus.
 20. A method for treating an angiotensin-related disease or disorder, wherein the angiotensin-related disease or disorder is a cardiovascular disease selected from the group consisting of myocardial infarction, congestive heart failure, diabetic cardiovascular disease, atrial fibrillation, hypertension, peripheral vascular disease, erectile dysfunction, stroke, pre-eclampsia, coated stents to inhibit restenosis, Marfan syndrome, and abdominal/thoracic aortic aneurysm, a metabolic disease selected from the group consisting of diabetes mellitus, insulin resistance and metabolic syndrome, a renal diseases selected from the group consisting of diabetic renal disease, drug-induced renal failure, and chronic renal failure, a pulmonary disease selected from the group consisting of pulmonary fibrosis, acute lung injury, pulmonary hypertension, and asthma, an inflammatory or autoimmune disease selected from the group consisting of arthritis, Crohn's disease, graft versus host disease, systemic sclerosis and multiple sclerosis, a neurological disease selected from the group consisting of depression, anxiety, dementia, Alzheimer's disease, neurodegenerative diseases, spinal cord injury, traumatic brain injury, peripheral neuropathy and Huntington's disease, a fibrotic disease selected from the group consisting of scar reduction, pulmonary fibrosis, liver fibrosis and cardiac fibrosis, a dermal disease selected from the group of wound healing, radiation mitigation, dermal repair, scar reduction, and alopecia, an ocular disease selected from the group consisting of macular degeneration, corneal scarring, diabetic ophthalmic disease, diabetes-related cardiovascular disorders, diabetes-related dermal ulcerations, diabetes-related hypertension, and diabetic retinopathy, a liver disease selected from the group consisting of non-alcoholic hepatosteatosis, hepatic fibrosis, hepatobilliary disease, fatty liver disease, cirrhosis, and liver fibrosis, cancer or supportive care for oncology, a gastrointestinal disease selected from the group consisting of ulcers and Crohn's disease, a bone marrow diseases selected from the group consisting of myelosuppression due to radiation or chemotherapy, autologous transplant, radiation mitigation, engraftment of transplant, allogenic transplant, engraftment, hematopoiesis and bone marrow injury, or an obesity-related disease or condition, comprising administering to the patient an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, to provide the needed therapeutic benefit. 